Clinical Inquiries

Evidence summary

Gestational diabetes mellitus is diagnosed when at least 2 of 4 values measured in a 3-hour glucose tolerance test are elevated; 2 different definitions of “elevated” are accepted (TABLE 1). White’s classification stratifies the risk of various types of diabetes during pregnancy (TABLE 2): Class A includes patients without a diagnosis of diabetes before pregnancy; classes B, C, and D include patients with pre-existing diabetes of increasing duration; and classes F, H, R, and T include patients with diabetes with various vascular complications.

Infants of mothers with pre-existing diabetes are at increased risk of pre- and neonatal complications (including stillbirth); it has been commonly assumed that type A1 gestational diabetes confers similar risks. However, 2 observational studies call this assumption into question. One study evaluated antepartum predictors of fetal distress requiring a cesarean delivery among 2134 pregnant women with gestational diabetes.⁴ Antepartum surveillance consisted of biweekly nonstress testing with amniotic fluid index determination starting at 34 weeks gestation. Of the 1501 eligible participants, the study included 810 and 580 class A1 and A2 patients, respectively; the remaining 111 were classes B–T. They considered women with A1 gestational diabetes with fasting plasma glucose levels <105 mg/dL to be well-controlled. Results of antepartum surveillance did not significantly differ among the different diabetic classes.

In univariate and multivariate analyses, the greatest indicator for cesarean section due to fetal distress was a nonreactive non-stress test with decelerations (odds ratio [OR]=5.63; 95% confidence interval [CI], 2.67–11.9). Routine amniotic fluid measurement was not significantly related to either the classification of diabetes or to cesarean delivery for fetal distress. No patients with normal surveillance testing within 4 days of delivery had a stillbirth. However, all 5 stillbirths in the study population occurred among those with A2 diabetes whose last non-stress test was >4 days prior.

An earlier retrospective study followed 97 pregnant patients with gestational diabetes, 69 of whom were diet-controlled (class A1, fasting glucose <105 mg/dL).⁵ Antepartum surveillance consisted of maternal monitoring and non-stress testing. At 28 weeks, pregnant patients assessed daily fetal activity; reassuring fetal well-being was defined as 10 fetal movements in a 12-hour period. At 40 weeks, a non-stress test was performed weekly. Contraction stress testing was performed for those with nonreactive non-stress tests. To observe for macrosomia, serial ultrasonography was performed every 4 to 6 weeks, starting at 28 weeks. Forty-four patients (64%) had spontaneous labors without intervention, while the rest required induction of labor or cesarean section (primary or failed induction). Five patients had primary cesarean section for suspected macrosomia, 3 patients had intervention for suspected intrauterine growth restriction, and only 4 (5.7%) patients were delivered due to fetal indications, defined as decreased fetal movement or a nonreactive nonstress test. No stillbirths or neonatal deaths occurred. Perinatal complications included hypoglycemia (n=13; 19%), hyperbilirubinemia (n=12; 17%), and macrosomia (n=11; 16%). The study did not compare complication rates between diet-controlled and insulin-requiring patients (SOR: B, retrospective study).

A Cochrane review found no evidence for or against increased surveillance in A1 gestational diabetes: “A lack of conclusive evidence has lead clinicians to equate the risk of adverse perinatal outcome with pre-existing diabetes. Consequently women are often managed with increased obstetrical monitoring, dietary regulation, and [pharmacological] treatment. However, no sound evidence base supports such intensive treatment.”⁶

TABLE
At least 2 of 4 measurements over 3 hours must be higher than these values to diagnose gestational diabetes mellitus

TABLE
White’s classification for gestational diabetes mellitus

Recommendations from others

The American College of Obstetricians and Gynecologists’ practice bulletin on gestational diabetes states that there is no consensus regarding fetal surveillance for women with diet-controlled gestational diabetes. However, local practice may include non-stress and contraction stress testing, amniotic fluid determination, and biophysical profile; this may start as early as 32 weeks to or as late as 40 weeks, based upon the total cumulative risk to the fetus from all potential complications.² The American Diabetes Association states that increased fetal surveillance is appropriate but is not any more specific with this recommendation.¹

Evidence summary

Gestational diabetes mellitus is diagnosed when at least 2 of 4 values measured in a 3-hour glucose tolerance test are elevated; 2 different definitions of “elevated” are accepted (TABLE 1). White’s classification stratifies the risk of various types of diabetes during pregnancy (TABLE 2): Class A includes patients without a diagnosis of diabetes before pregnancy; classes B, C, and D include patients with pre-existing diabetes of increasing duration; and classes F, H, R, and T include patients with diabetes with various vascular complications.

Infants of mothers with pre-existing diabetes are at increased risk of pre- and neonatal complications (including stillbirth); it has been commonly assumed that type A1 gestational diabetes confers similar risks. However, 2 observational studies call this assumption into question. One study evaluated antepartum predictors of fetal distress requiring a cesarean delivery among 2134 pregnant women with gestational diabetes.⁴ Antepartum surveillance consisted of biweekly nonstress testing with amniotic fluid index determination starting at 34 weeks gestation. Of the 1501 eligible participants, the study included 810 and 580 class A1 and A2 patients, respectively; the remaining 111 were classes B–T. They considered women with A1 gestational diabetes with fasting plasma glucose levels <105 mg/dL to be well-controlled. Results of antepartum surveillance did not significantly differ among the different diabetic classes.

In univariate and multivariate analyses, the greatest indicator for cesarean section due to fetal distress was a nonreactive non-stress test with decelerations (odds ratio [OR]=5.63; 95% confidence interval [CI], 2.67–11.9). Routine amniotic fluid measurement was not significantly related to either the classification of diabetes or to cesarean delivery for fetal distress. No patients with normal surveillance testing within 4 days of delivery had a stillbirth. However, all 5 stillbirths in the study population occurred among those with A2 diabetes whose last non-stress test was >4 days prior.

An earlier retrospective study followed 97 pregnant patients with gestational diabetes, 69 of whom were diet-controlled (class A1, fasting glucose <105 mg/dL).⁵ Antepartum surveillance consisted of maternal monitoring and non-stress testing. At 28 weeks, pregnant patients assessed daily fetal activity; reassuring fetal well-being was defined as 10 fetal movements in a 12-hour period. At 40 weeks, a non-stress test was performed weekly. Contraction stress testing was performed for those with nonreactive non-stress tests. To observe for macrosomia, serial ultrasonography was performed every 4 to 6 weeks, starting at 28 weeks. Forty-four patients (64%) had spontaneous labors without intervention, while the rest required induction of labor or cesarean section (primary or failed induction). Five patients had primary cesarean section for suspected macrosomia, 3 patients had intervention for suspected intrauterine growth restriction, and only 4 (5.7%) patients were delivered due to fetal indications, defined as decreased fetal movement or a nonreactive nonstress test. No stillbirths or neonatal deaths occurred. Perinatal complications included hypoglycemia (n=13; 19%), hyperbilirubinemia (n=12; 17%), and macrosomia (n=11; 16%). The study did not compare complication rates between diet-controlled and insulin-requiring patients (SOR: B, retrospective study).

A Cochrane review found no evidence for or against increased surveillance in A1 gestational diabetes: “A lack of conclusive evidence has lead clinicians to equate the risk of adverse perinatal outcome with pre-existing diabetes. Consequently women are often managed with increased obstetrical monitoring, dietary regulation, and [pharmacological] treatment. However, no sound evidence base supports such intensive treatment.”⁶

TABLE
At least 2 of 4 measurements over 3 hours must be higher than these values to diagnose gestational diabetes mellitus

TABLE
White’s classification for gestational diabetes mellitus

Recommendations from others

The American College of Obstetricians and Gynecologists’ practice bulletin on gestational diabetes states that there is no consensus regarding fetal surveillance for women with diet-controlled gestational diabetes. However, local practice may include non-stress and contraction stress testing, amniotic fluid determination, and biophysical profile; this may start as early as 32 weeks to or as late as 40 weeks, based upon the total cumulative risk to the fetus from all potential complications.² The American Diabetes Association states that increased fetal surveillance is appropriate but is not any more specific with this recommendation.¹

Evidence summary

Gestational diabetes mellitus is diagnosed when at least 2 of 4 values measured in a 3-hour glucose tolerance test are elevated; 2 different definitions of “elevated” are accepted (TABLE 1). White’s classification stratifies the risk of various types of diabetes during pregnancy (TABLE 2): Class A includes patients without a diagnosis of diabetes before pregnancy; classes B, C, and D include patients with pre-existing diabetes of increasing duration; and classes F, H, R, and T include patients with diabetes with various vascular complications.

Infants of mothers with pre-existing diabetes are at increased risk of pre- and neonatal complications (including stillbirth); it has been commonly assumed that type A1 gestational diabetes confers similar risks. However, 2 observational studies call this assumption into question. One study evaluated antepartum predictors of fetal distress requiring a cesarean delivery among 2134 pregnant women with gestational diabetes.⁴ Antepartum surveillance consisted of biweekly nonstress testing with amniotic fluid index determination starting at 34 weeks gestation. Of the 1501 eligible participants, the study included 810 and 580 class A1 and A2 patients, respectively; the remaining 111 were classes B–T. They considered women with A1 gestational diabetes with fasting plasma glucose levels <105 mg/dL to be well-controlled. Results of antepartum surveillance did not significantly differ among the different diabetic classes.

In univariate and multivariate analyses, the greatest indicator for cesarean section due to fetal distress was a nonreactive non-stress test with decelerations (odds ratio [OR]=5.63; 95% confidence interval [CI], 2.67–11.9). Routine amniotic fluid measurement was not significantly related to either the classification of diabetes or to cesarean delivery for fetal distress. No patients with normal surveillance testing within 4 days of delivery had a stillbirth. However, all 5 stillbirths in the study population occurred among those with A2 diabetes whose last non-stress test was >4 days prior.

An earlier retrospective study followed 97 pregnant patients with gestational diabetes, 69 of whom were diet-controlled (class A1, fasting glucose <105 mg/dL).⁵ Antepartum surveillance consisted of maternal monitoring and non-stress testing. At 28 weeks, pregnant patients assessed daily fetal activity; reassuring fetal well-being was defined as 10 fetal movements in a 12-hour period. At 40 weeks, a non-stress test was performed weekly. Contraction stress testing was performed for those with nonreactive non-stress tests. To observe for macrosomia, serial ultrasonography was performed every 4 to 6 weeks, starting at 28 weeks. Forty-four patients (64%) had spontaneous labors without intervention, while the rest required induction of labor or cesarean section (primary or failed induction). Five patients had primary cesarean section for suspected macrosomia, 3 patients had intervention for suspected intrauterine growth restriction, and only 4 (5.7%) patients were delivered due to fetal indications, defined as decreased fetal movement or a nonreactive nonstress test. No stillbirths or neonatal deaths occurred. Perinatal complications included hypoglycemia (n=13; 19%), hyperbilirubinemia (n=12; 17%), and macrosomia (n=11; 16%). The study did not compare complication rates between diet-controlled and insulin-requiring patients (SOR: B, retrospective study).

A Cochrane review found no evidence for or against increased surveillance in A1 gestational diabetes: “A lack of conclusive evidence has lead clinicians to equate the risk of adverse perinatal outcome with pre-existing diabetes. Consequently women are often managed with increased obstetrical monitoring, dietary regulation, and [pharmacological] treatment. However, no sound evidence base supports such intensive treatment.”⁶

TABLE
At least 2 of 4 measurements over 3 hours must be higher than these values to diagnose gestational diabetes mellitus

TABLE
White’s classification for gestational diabetes mellitus

Recommendations from others

The American College of Obstetricians and Gynecologists’ practice bulletin on gestational diabetes states that there is no consensus regarding fetal surveillance for women with diet-controlled gestational diabetes. However, local practice may include non-stress and contraction stress testing, amniotic fluid determination, and biophysical profile; this may start as early as 32 weeks to or as late as 40 weeks, based upon the total cumulative risk to the fetus from all potential complications.² The American Diabetes Association states that increased fetal surveillance is appropriate but is not any more specific with this recommendation.¹

Evidence summary

Amitriptyline and other tricyclic and tetracyclic antidepressants moderately improve pain control for patients with chronic back pain.^1,2 The pain reduction was independent of the presence of depression, although patients who were depressed had a significant improvement in mood. The outcome on chronic pain of antidepressants with serotonin and norepinephrine reuptake inhibitory activity is still being evaluated. It appears that those with only SSRI activity are not effective improving chronic pain.²

Tricyclics are effective for diabetic neuropathy (number needed to treat [NNT]=3.5 for 50% reduction of pain),³ and they are effective for reducing pain but not for global symptoms in irritable bowel syndrome.⁴ Amitriptyline reduces the pain of diabetic peripheral neuropathy in a dose related manner up to 150 mg/d, although much lower doses are often effective and cause fewer anticholinergic side-effects.

For chronic back pain, a Cochrane review including 1964 patients found strong evidence for pain reduction and modest evidence for functional improvement from intensive (>100 hours) multidisciplinary biopsychosocial rehabilitation. Less intense and less comprehensive psychophysical programs did not reduce pain or improve function.⁵ It was unclear if the intensive programs were generalizable. Another review found that cognitive and progressive relaxation therapy had a moderate effect on short-term pain control vs waiting-list controls for chronic back pain. However, only a third of the studies were of “high quality,” and the total number of patients in the relaxation analysis was 39.⁶

A systematic review of 25 studies (1672 patients) found significant effect sizes for cognitive therapies in reducing pain and other symptoms in chronic musculoskeletal pain, including rheumatoid arthritis, fibromyalgia, back, and other pain syndromes.⁷ However, many of the trials were small or taken from “samples of convenience” from rehabilitation and pain clinics, and most lacked documentation of randomization. For rheumatoid arthritis alone, a systematic review of 19 studies found cognitive therapies had a small but statistically significant effect on pain, functional disability, depression, coping, and self-efficacy for 1298 patients at initial follow-up. However, only “tender points” and coping remained improved at subsequent follow-ups averaging 8.5 months.⁸

In adults with cancer pain, a recent meta-analysis of 1723 patients showed modest but significant effects on pain from psycho-educational interventions in 25 studies.⁹ Although just 3 of the studies lasted 52 weeks or longer, effects were found from good-quality studies for “relaxation-promoting,” educational, and supportive counseling plus content therapies.

A significant confounder in many of these studies may be that some treatments seem more effective in secondary care than in primary care settings, as based on a systemic review of interventions for somatic symptoms in primary care.¹⁰

Recommendations from others

The NIH states that antidepressants are effective adjuvants in pain management, and that cognitive-behavioral treatments may be beneficial.¹¹ The American Society of Anesthesiology states that “the literature supports the use of antidepressants for reducing chronic pain without notable adverse effects.”¹² The Arthritis Foundation lists amitriptyline, duloxetine, fluoxetine, and paroxetine as treatment options for pain and for helping sleep in fibromyalgia.¹³

Evidence summary

Amitriptyline and other tricyclic and tetracyclic antidepressants moderately improve pain control for patients with chronic back pain.^1,2 The pain reduction was independent of the presence of depression, although patients who were depressed had a significant improvement in mood. The outcome on chronic pain of antidepressants with serotonin and norepinephrine reuptake inhibitory activity is still being evaluated. It appears that those with only SSRI activity are not effective improving chronic pain.²

Tricyclics are effective for diabetic neuropathy (number needed to treat [NNT]=3.5 for 50% reduction of pain),³ and they are effective for reducing pain but not for global symptoms in irritable bowel syndrome.⁴ Amitriptyline reduces the pain of diabetic peripheral neuropathy in a dose related manner up to 150 mg/d, although much lower doses are often effective and cause fewer anticholinergic side-effects.

For chronic back pain, a Cochrane review including 1964 patients found strong evidence for pain reduction and modest evidence for functional improvement from intensive (>100 hours) multidisciplinary biopsychosocial rehabilitation. Less intense and less comprehensive psychophysical programs did not reduce pain or improve function.⁵ It was unclear if the intensive programs were generalizable. Another review found that cognitive and progressive relaxation therapy had a moderate effect on short-term pain control vs waiting-list controls for chronic back pain. However, only a third of the studies were of “high quality,” and the total number of patients in the relaxation analysis was 39.⁶

A systematic review of 25 studies (1672 patients) found significant effect sizes for cognitive therapies in reducing pain and other symptoms in chronic musculoskeletal pain, including rheumatoid arthritis, fibromyalgia, back, and other pain syndromes.⁷ However, many of the trials were small or taken from “samples of convenience” from rehabilitation and pain clinics, and most lacked documentation of randomization. For rheumatoid arthritis alone, a systematic review of 19 studies found cognitive therapies had a small but statistically significant effect on pain, functional disability, depression, coping, and self-efficacy for 1298 patients at initial follow-up. However, only “tender points” and coping remained improved at subsequent follow-ups averaging 8.5 months.⁸

In adults with cancer pain, a recent meta-analysis of 1723 patients showed modest but significant effects on pain from psycho-educational interventions in 25 studies.⁹ Although just 3 of the studies lasted 52 weeks or longer, effects were found from good-quality studies for “relaxation-promoting,” educational, and supportive counseling plus content therapies.

A significant confounder in many of these studies may be that some treatments seem more effective in secondary care than in primary care settings, as based on a systemic review of interventions for somatic symptoms in primary care.¹⁰

Recommendations from others

The NIH states that antidepressants are effective adjuvants in pain management, and that cognitive-behavioral treatments may be beneficial.¹¹ The American Society of Anesthesiology states that “the literature supports the use of antidepressants for reducing chronic pain without notable adverse effects.”¹² The Arthritis Foundation lists amitriptyline, duloxetine, fluoxetine, and paroxetine as treatment options for pain and for helping sleep in fibromyalgia.¹³

Evidence summary

Amitriptyline and other tricyclic and tetracyclic antidepressants moderately improve pain control for patients with chronic back pain.^1,2 The pain reduction was independent of the presence of depression, although patients who were depressed had a significant improvement in mood. The outcome on chronic pain of antidepressants with serotonin and norepinephrine reuptake inhibitory activity is still being evaluated. It appears that those with only SSRI activity are not effective improving chronic pain.²

Tricyclics are effective for diabetic neuropathy (number needed to treat [NNT]=3.5 for 50% reduction of pain),³ and they are effective for reducing pain but not for global symptoms in irritable bowel syndrome.⁴ Amitriptyline reduces the pain of diabetic peripheral neuropathy in a dose related manner up to 150 mg/d, although much lower doses are often effective and cause fewer anticholinergic side-effects.

For chronic back pain, a Cochrane review including 1964 patients found strong evidence for pain reduction and modest evidence for functional improvement from intensive (>100 hours) multidisciplinary biopsychosocial rehabilitation. Less intense and less comprehensive psychophysical programs did not reduce pain or improve function.⁵ It was unclear if the intensive programs were generalizable. Another review found that cognitive and progressive relaxation therapy had a moderate effect on short-term pain control vs waiting-list controls for chronic back pain. However, only a third of the studies were of “high quality,” and the total number of patients in the relaxation analysis was 39.⁶

A systematic review of 25 studies (1672 patients) found significant effect sizes for cognitive therapies in reducing pain and other symptoms in chronic musculoskeletal pain, including rheumatoid arthritis, fibromyalgia, back, and other pain syndromes.⁷ However, many of the trials were small or taken from “samples of convenience” from rehabilitation and pain clinics, and most lacked documentation of randomization. For rheumatoid arthritis alone, a systematic review of 19 studies found cognitive therapies had a small but statistically significant effect on pain, functional disability, depression, coping, and self-efficacy for 1298 patients at initial follow-up. However, only “tender points” and coping remained improved at subsequent follow-ups averaging 8.5 months.⁸

In adults with cancer pain, a recent meta-analysis of 1723 patients showed modest but significant effects on pain from psycho-educational interventions in 25 studies.⁹ Although just 3 of the studies lasted 52 weeks or longer, effects were found from good-quality studies for “relaxation-promoting,” educational, and supportive counseling plus content therapies.

A significant confounder in many of these studies may be that some treatments seem more effective in secondary care than in primary care settings, as based on a systemic review of interventions for somatic symptoms in primary care.¹⁰

Recommendations from others

The NIH states that antidepressants are effective adjuvants in pain management, and that cognitive-behavioral treatments may be beneficial.¹¹ The American Society of Anesthesiology states that “the literature supports the use of antidepressants for reducing chronic pain without notable adverse effects.”¹² The Arthritis Foundation lists amitriptyline, duloxetine, fluoxetine, and paroxetine as treatment options for pain and for helping sleep in fibromyalgia.¹³

Evidence summary

No published studies compare varying durations of treatment with steroids for contact dermatitis due to plants, including rhus. Many review articles refer to rebound dermatitis when using courses of oral steroids (such as Medrol dosepaks) for fewer than 14 days. One case report noted failure of a tapering dose over 5 days of oral methylprednisolone for treatment of poison ivy contact dermatitis.²

Most review articles recommend systemic steroids for severe poison ivy contact dermatitis, but these articles do not define “severe,” describe the taper, or give a definite length of treatment.^3-5 One review recommends a tapering dose of oral prednisone to prevent rebound recurrence if the rash affects >25% of the body surface area, has severe blistering or itching, or significantly involves the face, hands, or genital area. That review suggests starting with oral prednisone 60 mg/d for 4 days, followed by a 10-day taper (50 mg/d for 2 days, 40 mg/d for 2 days, 30 mg/d for 2 days, 20 mg/d for 2 days, then 10 mg/d for 2 days).³

Another review recommends using systemic steroids for severe cases, defined as involvement of greater than 20% of total body surface area, bullae formation, or extensive facial involvement. That review recommends a starting dose of 1 mg/kg/d, or 40 to 60 mg/d in adults, followed by a 2- to 3-week taper of oral prednisone.⁴ A third review recommends using prednisone for children with allergic contact dermatitis involving more than 10% of the total body surface area.⁵

Recommendations from others

Guidelines for treatment of contact dermatitis published by the American Academy of Dermatology recommend topical treatment alone for mild cases of contact dermatitis, defined as “limited site of involvement, acute contact dermatitis when the offending agent has been removed, or chronic contact dermatitis with limited symptoms.” The guideline states that systemic treatment may be indicated to control itching or edema, or for moderate to severe cases. The systemic treatments listed include oral or intramuscular corticosteroids, but no discussion of duration is mentioned.⁶

UpToDate discusses avoidance of the offending substance for 2 to 4 weeks, use of topical corticosteroids of medium to strong potency for a limited time (without defining the duration), and use of systemic corticosteroids in severe cases, prescribing a course of prednisone at 40 mg daily for 4 to 6 days followed by 20 mg for 4 to 6 days.⁷

eMedicine states that although oral systemic steroids, with a taper of prednisone over 10 to 14 days, are the standard for severe toxicodendron dermatitis, some authors suggest high-potency steroid creams twice daily for a week, then daily for a week.⁸

ACP Medicine states that most cases of allergic contact dermatitis are “effectively managed without use of systemic corticosteroids,” but that “short courses of systemic corticosteroids are indicated for patients with severe vesiculobullous eruptions of the hands and feet or face,” without describing duration or dose.⁹

Evidence summary

No published studies compare varying durations of treatment with steroids for contact dermatitis due to plants, including rhus. Many review articles refer to rebound dermatitis when using courses of oral steroids (such as Medrol dosepaks) for fewer than 14 days. One case report noted failure of a tapering dose over 5 days of oral methylprednisolone for treatment of poison ivy contact dermatitis.²

Most review articles recommend systemic steroids for severe poison ivy contact dermatitis, but these articles do not define “severe,” describe the taper, or give a definite length of treatment.^3-5 One review recommends a tapering dose of oral prednisone to prevent rebound recurrence if the rash affects >25% of the body surface area, has severe blistering or itching, or significantly involves the face, hands, or genital area. That review suggests starting with oral prednisone 60 mg/d for 4 days, followed by a 10-day taper (50 mg/d for 2 days, 40 mg/d for 2 days, 30 mg/d for 2 days, 20 mg/d for 2 days, then 10 mg/d for 2 days).³

Another review recommends using systemic steroids for severe cases, defined as involvement of greater than 20% of total body surface area, bullae formation, or extensive facial involvement. That review recommends a starting dose of 1 mg/kg/d, or 40 to 60 mg/d in adults, followed by a 2- to 3-week taper of oral prednisone.⁴ A third review recommends using prednisone for children with allergic contact dermatitis involving more than 10% of the total body surface area.⁵

Recommendations from others

Guidelines for treatment of contact dermatitis published by the American Academy of Dermatology recommend topical treatment alone for mild cases of contact dermatitis, defined as “limited site of involvement, acute contact dermatitis when the offending agent has been removed, or chronic contact dermatitis with limited symptoms.” The guideline states that systemic treatment may be indicated to control itching or edema, or for moderate to severe cases. The systemic treatments listed include oral or intramuscular corticosteroids, but no discussion of duration is mentioned.⁶

UpToDate discusses avoidance of the offending substance for 2 to 4 weeks, use of topical corticosteroids of medium to strong potency for a limited time (without defining the duration), and use of systemic corticosteroids in severe cases, prescribing a course of prednisone at 40 mg daily for 4 to 6 days followed by 20 mg for 4 to 6 days.⁷

eMedicine states that although oral systemic steroids, with a taper of prednisone over 10 to 14 days, are the standard for severe toxicodendron dermatitis, some authors suggest high-potency steroid creams twice daily for a week, then daily for a week.⁸

ACP Medicine states that most cases of allergic contact dermatitis are “effectively managed without use of systemic corticosteroids,” but that “short courses of systemic corticosteroids are indicated for patients with severe vesiculobullous eruptions of the hands and feet or face,” without describing duration or dose.⁹

Evidence summary

No published studies compare varying durations of treatment with steroids for contact dermatitis due to plants, including rhus. Many review articles refer to rebound dermatitis when using courses of oral steroids (such as Medrol dosepaks) for fewer than 14 days. One case report noted failure of a tapering dose over 5 days of oral methylprednisolone for treatment of poison ivy contact dermatitis.²

Most review articles recommend systemic steroids for severe poison ivy contact dermatitis, but these articles do not define “severe,” describe the taper, or give a definite length of treatment.^3-5 One review recommends a tapering dose of oral prednisone to prevent rebound recurrence if the rash affects >25% of the body surface area, has severe blistering or itching, or significantly involves the face, hands, or genital area. That review suggests starting with oral prednisone 60 mg/d for 4 days, followed by a 10-day taper (50 mg/d for 2 days, 40 mg/d for 2 days, 30 mg/d for 2 days, 20 mg/d for 2 days, then 10 mg/d for 2 days).³

Another review recommends using systemic steroids for severe cases, defined as involvement of greater than 20% of total body surface area, bullae formation, or extensive facial involvement. That review recommends a starting dose of 1 mg/kg/d, or 40 to 60 mg/d in adults, followed by a 2- to 3-week taper of oral prednisone.⁴ A third review recommends using prednisone for children with allergic contact dermatitis involving more than 10% of the total body surface area.⁵

Recommendations from others

Guidelines for treatment of contact dermatitis published by the American Academy of Dermatology recommend topical treatment alone for mild cases of contact dermatitis, defined as “limited site of involvement, acute contact dermatitis when the offending agent has been removed, or chronic contact dermatitis with limited symptoms.” The guideline states that systemic treatment may be indicated to control itching or edema, or for moderate to severe cases. The systemic treatments listed include oral or intramuscular corticosteroids, but no discussion of duration is mentioned.⁶

UpToDate discusses avoidance of the offending substance for 2 to 4 weeks, use of topical corticosteroids of medium to strong potency for a limited time (without defining the duration), and use of systemic corticosteroids in severe cases, prescribing a course of prednisone at 40 mg daily for 4 to 6 days followed by 20 mg for 4 to 6 days.⁷

eMedicine states that although oral systemic steroids, with a taper of prednisone over 10 to 14 days, are the standard for severe toxicodendron dermatitis, some authors suggest high-potency steroid creams twice daily for a week, then daily for a week.⁸

ACP Medicine states that most cases of allergic contact dermatitis are “effectively managed without use of systemic corticosteroids,” but that “short courses of systemic corticosteroids are indicated for patients with severe vesiculobullous eruptions of the hands and feet or face,” without describing duration or dose.⁹

Evidence summary

Clinical evaluation with medical history and physical exam, chest radiography, and selected sputum sampling to exclude active tuberculosis are part of the recommended algorithm for all patients who develop a positive PPD (FIGURE).^1-3 These recommendations are derived from expert opinion, and their usefulness has not been evaluated in any population-based study of asymptomatic PPD-positive patients.

A comprehensive review of RCTs from the 1950s and 1960s demonstrated that INH treatment of patients with latent tuberculosis infection is effective in decreasing the progression to active tuberculosis.⁴ A series of double-blinded RCTs performed by the US Public Health Service included 25,923 patients with latent tuberculosis who were randomized to receive either daily INH or placebo for 1 year with 6- to 10-year follow-up. Groups studied included household contacts of patients with active tuberculosis (rate of progression to active disease in placebo group [baseline rate]=27/1000, relative risk with INH [RR]=0.4, number needed to treat [NNT]=63), patients in mental institutions (baseline rate=12/1000, RR=0.3, NNT=121), and patients with x-ray findings of healed tuberculosis (baseline rate=69/1000, RR=0.4, NNT=23).

The optimal length of treatment for PPD-positive patients without active disease was evaluated through 1 double-blinded RCT enrolling 28,000 patients with 5-year follow-up after 12, 24, or 52 weeks of INH or placebo. Active TB developed in 0.35% (24/6919) after 52 weeks of INH compared with 0.49% (34/6965) after 24 weeks (RR=1.4, NNT=708).⁵ Incidence in the placebo group was 1.4%. Subgroup analysis determined that maximum efficacy with fewest side effects was achieved at 9 months.⁶ Nine months of INH is also recommended for HIV-positive patients, based on extrapolations from these and other studies.³

INH monotherapy was compared with combination INH and rifampin in a 2005 meta-analysis of 5 RCTs of variable quality involving 1926 patients.⁷ This meta-analysis found equivalency in risk of active TB and mortality between INH monotherapy for 6 to 12 months and the combination of rifampin and INH for 3 months (pooled risk difference=0%; 95% confidence interval [CI], –1% to 2%). This study also showed similar rates of adverse events in both groups (pooled risk difference=–1%; 95% CI, –7% to 5%). Short-course combination rifampin and pyrazinamide is no longer recommended after an open-label RCT with 589 patients demonstrated severe hepatoxicity in 7.7% (16/207) on a 2-month course of pyrazinamide and rifampin, compared with 1% (2/204) on 6 months of INH (RR=7.9, number needed to harm=15).⁸ Rifampin monotherapy has only been studied in patients with silicosis in a RCT enrolling 652 participants with latent tuberculosis. A 12-week course of rifampin (600 mg daily) was as effective as 6 months of INH in preventing development of active TB over the next 5 years.⁹

FIGURE
Suggested workup of asymptomatic, HIV-negative patients with a positive PPD

Recommendations from others

Centers for Disease Control and Prevention, American Thoracic Society, and Infectious Disease Society of America guidelines recommend targeted screening of high-risk persons followed by further clinical evaluation of all those with a reactive PPD (FIGURE).^2,10 The recommended treatment regimen for latent TB is daily INH for 9 months. Less preferable regimens are daily INH for 6 months, or daily rifampin for 4 months in patients who cannot tolerate INH. A 2-month course of rifampin and pyrazinamide is no longer recommended. The recent meta-analysis supporting a 3-month regimen of combination INH and rifampin has not been incorporated into expert guidelines.⁷

Evidence summary

Clinical evaluation with medical history and physical exam, chest radiography, and selected sputum sampling to exclude active tuberculosis are part of the recommended algorithm for all patients who develop a positive PPD (FIGURE).^1-3 These recommendations are derived from expert opinion, and their usefulness has not been evaluated in any population-based study of asymptomatic PPD-positive patients.

A comprehensive review of RCTs from the 1950s and 1960s demonstrated that INH treatment of patients with latent tuberculosis infection is effective in decreasing the progression to active tuberculosis.⁴ A series of double-blinded RCTs performed by the US Public Health Service included 25,923 patients with latent tuberculosis who were randomized to receive either daily INH or placebo for 1 year with 6- to 10-year follow-up. Groups studied included household contacts of patients with active tuberculosis (rate of progression to active disease in placebo group [baseline rate]=27/1000, relative risk with INH [RR]=0.4, number needed to treat [NNT]=63), patients in mental institutions (baseline rate=12/1000, RR=0.3, NNT=121), and patients with x-ray findings of healed tuberculosis (baseline rate=69/1000, RR=0.4, NNT=23).

The optimal length of treatment for PPD-positive patients without active disease was evaluated through 1 double-blinded RCT enrolling 28,000 patients with 5-year follow-up after 12, 24, or 52 weeks of INH or placebo. Active TB developed in 0.35% (24/6919) after 52 weeks of INH compared with 0.49% (34/6965) after 24 weeks (RR=1.4, NNT=708).⁵ Incidence in the placebo group was 1.4%. Subgroup analysis determined that maximum efficacy with fewest side effects was achieved at 9 months.⁶ Nine months of INH is also recommended for HIV-positive patients, based on extrapolations from these and other studies.³

INH monotherapy was compared with combination INH and rifampin in a 2005 meta-analysis of 5 RCTs of variable quality involving 1926 patients.⁷ This meta-analysis found equivalency in risk of active TB and mortality between INH monotherapy for 6 to 12 months and the combination of rifampin and INH for 3 months (pooled risk difference=0%; 95% confidence interval [CI], –1% to 2%). This study also showed similar rates of adverse events in both groups (pooled risk difference=–1%; 95% CI, –7% to 5%). Short-course combination rifampin and pyrazinamide is no longer recommended after an open-label RCT with 589 patients demonstrated severe hepatoxicity in 7.7% (16/207) on a 2-month course of pyrazinamide and rifampin, compared with 1% (2/204) on 6 months of INH (RR=7.9, number needed to harm=15).⁸ Rifampin monotherapy has only been studied in patients with silicosis in a RCT enrolling 652 participants with latent tuberculosis. A 12-week course of rifampin (600 mg daily) was as effective as 6 months of INH in preventing development of active TB over the next 5 years.⁹

FIGURE
Suggested workup of asymptomatic, HIV-negative patients with a positive PPD

Recommendations from others

Centers for Disease Control and Prevention, American Thoracic Society, and Infectious Disease Society of America guidelines recommend targeted screening of high-risk persons followed by further clinical evaluation of all those with a reactive PPD (FIGURE).^2,10 The recommended treatment regimen for latent TB is daily INH for 9 months. Less preferable regimens are daily INH for 6 months, or daily rifampin for 4 months in patients who cannot tolerate INH. A 2-month course of rifampin and pyrazinamide is no longer recommended. The recent meta-analysis supporting a 3-month regimen of combination INH and rifampin has not been incorporated into expert guidelines.⁷

Evidence summary

Clinical evaluation with medical history and physical exam, chest radiography, and selected sputum sampling to exclude active tuberculosis are part of the recommended algorithm for all patients who develop a positive PPD (FIGURE).^1-3 These recommendations are derived from expert opinion, and their usefulness has not been evaluated in any population-based study of asymptomatic PPD-positive patients.

A comprehensive review of RCTs from the 1950s and 1960s demonstrated that INH treatment of patients with latent tuberculosis infection is effective in decreasing the progression to active tuberculosis.⁴ A series of double-blinded RCTs performed by the US Public Health Service included 25,923 patients with latent tuberculosis who were randomized to receive either daily INH or placebo for 1 year with 6- to 10-year follow-up. Groups studied included household contacts of patients with active tuberculosis (rate of progression to active disease in placebo group [baseline rate]=27/1000, relative risk with INH [RR]=0.4, number needed to treat [NNT]=63), patients in mental institutions (baseline rate=12/1000, RR=0.3, NNT=121), and patients with x-ray findings of healed tuberculosis (baseline rate=69/1000, RR=0.4, NNT=23).

The optimal length of treatment for PPD-positive patients without active disease was evaluated through 1 double-blinded RCT enrolling 28,000 patients with 5-year follow-up after 12, 24, or 52 weeks of INH or placebo. Active TB developed in 0.35% (24/6919) after 52 weeks of INH compared with 0.49% (34/6965) after 24 weeks (RR=1.4, NNT=708).⁵ Incidence in the placebo group was 1.4%. Subgroup analysis determined that maximum efficacy with fewest side effects was achieved at 9 months.⁶ Nine months of INH is also recommended for HIV-positive patients, based on extrapolations from these and other studies.³

INH monotherapy was compared with combination INH and rifampin in a 2005 meta-analysis of 5 RCTs of variable quality involving 1926 patients.⁷ This meta-analysis found equivalency in risk of active TB and mortality between INH monotherapy for 6 to 12 months and the combination of rifampin and INH for 3 months (pooled risk difference=0%; 95% confidence interval [CI], –1% to 2%). This study also showed similar rates of adverse events in both groups (pooled risk difference=–1%; 95% CI, –7% to 5%). Short-course combination rifampin and pyrazinamide is no longer recommended after an open-label RCT with 589 patients demonstrated severe hepatoxicity in 7.7% (16/207) on a 2-month course of pyrazinamide and rifampin, compared with 1% (2/204) on 6 months of INH (RR=7.9, number needed to harm=15).⁸ Rifampin monotherapy has only been studied in patients with silicosis in a RCT enrolling 652 participants with latent tuberculosis. A 12-week course of rifampin (600 mg daily) was as effective as 6 months of INH in preventing development of active TB over the next 5 years.⁹

FIGURE
Suggested workup of asymptomatic, HIV-negative patients with a positive PPD

Recommendations from others

Centers for Disease Control and Prevention, American Thoracic Society, and Infectious Disease Society of America guidelines recommend targeted screening of high-risk persons followed by further clinical evaluation of all those with a reactive PPD (FIGURE).^2,10 The recommended treatment regimen for latent TB is daily INH for 9 months. Less preferable regimens are daily INH for 6 months, or daily rifampin for 4 months in patients who cannot tolerate INH. A 2-month course of rifampin and pyrazinamide is no longer recommended. The recent meta-analysis supporting a 3-month regimen of combination INH and rifampin has not been incorporated into expert guidelines.⁷

Evidence summary

Increased risk of falling is often given as a reason for not recommending anticoagulation for atrial fibrillation in frail or elderly patients. However, no studies directly address the risk for major bleeding in anticoagulated patients who fall.

One retrospective study of 2633 falls in 1861 hospital inpatients compared the rate of major hemorrhage between those taking anticoagulation therapy with those not taking it.¹ Major hemorrhage was defined as bruising or cuts requiring immediate attention from a physician. The rate of major hemorrhage was 6.2% for patients taking warfarin and 11.3% for patients receiving no therapy. Patients with INR=2–3 had a major hemorrhage rate of 6.9% compared with 10.1% for those with INR <1.3. Criteria for using warfarin were not reported; there may have been selection bias in favor of prescribing warfarin for patients judged less likely to fall.

A smaller study of 400 consecutive falls among 264 post-stroke patients in a rehab hospital found no difference in minor injury rates (19% vs 18%, NS); no major hemorrhagic complications were seen following 131 falls in the anticoagulation group (93 patients) and 269 falls in the group not on anticoagulation (175 patients).² Patients on anticoagulation had an average protime of 16.1 seconds (INR was not reported). The calculated risk of major hemorrhage in an anticoagulated patient from a single fall was 2.3% or less. The study was limited because most falls were from a seated position or partially controlled by an attendant; few patients fell from a standing position.

Another study presented a Markov decision analysis (comparison of risk estimates in separate disease states) evaluating whether risk from falls should influence choice of anticoagulation therapy in elderly patients with atrial fibrillation.³ Risk of intracranial bleeding from falls was calculated from prospective cohort studies and retrospective case series from anticoagulation clinics, and stroke reduction benefit from anticoagulation was taken from a meta-analysis of 5 randomized controlled trials. Sensitivity analyses were performed to test the results of the decision analysis. The calculated risk of subdural hematoma from falling was such that a patient with a 5% annual stroke risk from atrial fibrillation would need to fall 295 times in a year for the fall risk to outweigh the stroke reduction benefit of warfarin.

Recommendations from others

Guidelines from the American Heart Association and the American College of Chest Physicians do not include fall risk in the decision to use anticoagulation.⁴

Guidelines from the Institute for Clinical Systems Improvement note that patients with 3 falls in the previous year or with recurrent, injurious falls were excluded from trials evaluating efficacy and safety of anticoagulation in patients with nonvalvular atrial fibrillation.⁵

Evidence summary

Increased risk of falling is often given as a reason for not recommending anticoagulation for atrial fibrillation in frail or elderly patients. However, no studies directly address the risk for major bleeding in anticoagulated patients who fall.

One retrospective study of 2633 falls in 1861 hospital inpatients compared the rate of major hemorrhage between those taking anticoagulation therapy with those not taking it.¹ Major hemorrhage was defined as bruising or cuts requiring immediate attention from a physician. The rate of major hemorrhage was 6.2% for patients taking warfarin and 11.3% for patients receiving no therapy. Patients with INR=2–3 had a major hemorrhage rate of 6.9% compared with 10.1% for those with INR <1.3. Criteria for using warfarin were not reported; there may have been selection bias in favor of prescribing warfarin for patients judged less likely to fall.

A smaller study of 400 consecutive falls among 264 post-stroke patients in a rehab hospital found no difference in minor injury rates (19% vs 18%, NS); no major hemorrhagic complications were seen following 131 falls in the anticoagulation group (93 patients) and 269 falls in the group not on anticoagulation (175 patients).² Patients on anticoagulation had an average protime of 16.1 seconds (INR was not reported). The calculated risk of major hemorrhage in an anticoagulated patient from a single fall was 2.3% or less. The study was limited because most falls were from a seated position or partially controlled by an attendant; few patients fell from a standing position.

Another study presented a Markov decision analysis (comparison of risk estimates in separate disease states) evaluating whether risk from falls should influence choice of anticoagulation therapy in elderly patients with atrial fibrillation.³ Risk of intracranial bleeding from falls was calculated from prospective cohort studies and retrospective case series from anticoagulation clinics, and stroke reduction benefit from anticoagulation was taken from a meta-analysis of 5 randomized controlled trials. Sensitivity analyses were performed to test the results of the decision analysis. The calculated risk of subdural hematoma from falling was such that a patient with a 5% annual stroke risk from atrial fibrillation would need to fall 295 times in a year for the fall risk to outweigh the stroke reduction benefit of warfarin.

Recommendations from others

Guidelines from the American Heart Association and the American College of Chest Physicians do not include fall risk in the decision to use anticoagulation.⁴

Guidelines from the Institute for Clinical Systems Improvement note that patients with 3 falls in the previous year or with recurrent, injurious falls were excluded from trials evaluating efficacy and safety of anticoagulation in patients with nonvalvular atrial fibrillation.⁵

Evidence summary

Increased risk of falling is often given as a reason for not recommending anticoagulation for atrial fibrillation in frail or elderly patients. However, no studies directly address the risk for major bleeding in anticoagulated patients who fall.

One retrospective study of 2633 falls in 1861 hospital inpatients compared the rate of major hemorrhage between those taking anticoagulation therapy with those not taking it.¹ Major hemorrhage was defined as bruising or cuts requiring immediate attention from a physician. The rate of major hemorrhage was 6.2% for patients taking warfarin and 11.3% for patients receiving no therapy. Patients with INR=2–3 had a major hemorrhage rate of 6.9% compared with 10.1% for those with INR <1.3. Criteria for using warfarin were not reported; there may have been selection bias in favor of prescribing warfarin for patients judged less likely to fall.

A smaller study of 400 consecutive falls among 264 post-stroke patients in a rehab hospital found no difference in minor injury rates (19% vs 18%, NS); no major hemorrhagic complications were seen following 131 falls in the anticoagulation group (93 patients) and 269 falls in the group not on anticoagulation (175 patients).² Patients on anticoagulation had an average protime of 16.1 seconds (INR was not reported). The calculated risk of major hemorrhage in an anticoagulated patient from a single fall was 2.3% or less. The study was limited because most falls were from a seated position or partially controlled by an attendant; few patients fell from a standing position.

Another study presented a Markov decision analysis (comparison of risk estimates in separate disease states) evaluating whether risk from falls should influence choice of anticoagulation therapy in elderly patients with atrial fibrillation.³ Risk of intracranial bleeding from falls was calculated from prospective cohort studies and retrospective case series from anticoagulation clinics, and stroke reduction benefit from anticoagulation was taken from a meta-analysis of 5 randomized controlled trials. Sensitivity analyses were performed to test the results of the decision analysis. The calculated risk of subdural hematoma from falling was such that a patient with a 5% annual stroke risk from atrial fibrillation would need to fall 295 times in a year for the fall risk to outweigh the stroke reduction benefit of warfarin.

Recommendations from others

Guidelines from the American Heart Association and the American College of Chest Physicians do not include fall risk in the decision to use anticoagulation.⁴

Guidelines from the Institute for Clinical Systems Improvement note that patients with 3 falls in the previous year or with recurrent, injurious falls were excluded from trials evaluating efficacy and safety of anticoagulation in patients with nonvalvular atrial fibrillation.⁵

Evidence summary

Many serum markers and screening methods have been proposed to detect hepatocellular carcinoma at a treatable stage, but only 2—AFP and US—are in clinical use.¹

A Cochrane systematic review on screening for hepatocellular carcinoma in the HBsAg+ population was published in 2003 and updated May 2004.² Our literature search did not find any subsequent relevant trials. The Cochrane review included 2 randomized control trials. The larger trial was performed in Shanghai, China and included 18,816 HBsAg+ patients aged 35 to 55 years.³ Subjects were recruited from their place of employment and randomized to either AFP/US every 6 months (n=9373) or to no screening (n=9443).

Fifty-one hepatocellular carcinomas were diagnosed in the control group and 86 in screened group. Screened subjects had a significantly higher percentage of tumors that were less than 5 cm at the time of diagnosis and a higher number of patients who underwent resection. While the 5-year survival for those with hepatocellular carcinoma in the screened group was higher, the disease-specific mortality rate was not statistically different between the 2 groups.

Additional data became available in 2002. The original study authors claimed the new data showed a statistically significant disease-specific mortality rate ratio of 0.63, favoring the screened group.⁴ However, the Cochrane group performed their own analysis on the same data and determined that no statistically significant difference in the disease-specific mortality rates existed between the 2 groups.² Therefore, it is not clear whether these new data definitively demonstrate that screening provides any benefit.

The other randomized control trial took place in Toronto, and included 1069 patients, 71% of whom were of Asian ancestry. Subjects had AFP testing every 6 months, and half were randomly assigned to have US performed every 6 months.⁵ Eight of the 11 incident tumors would have been diagnosed based on AFP levels alone, and 3 would have been missed with US alone. The authors conclude that for AFP, sensitivity=64.3% and specificity=91.4%; for US, sensitivity=78.8% and specificity=93.8%. However, their study was too small to determine if AFP/US is superior to AFP for hepatocellular carcinoma screening in a HBsAg+ population. They estimate that detecting such a difference would take a sample size of 10,000 or more.

Both studies have important flaws. Neither study applied a reference standard test (such as a computed tomography scan or magnetic resonance imaging) to both study arms. Carcinomas may have been undetected by either AFP or US. Without knowing the real prevalence of hepatocellular carcinoma, the true sensitivity and specificity for AFP, US, and AFP/US in these studies cannot be determined. Both studies included prevalent tumors (tumors diagnosed during the very first screening cycle) in their analysis. Approximately 20% of detected carcinomas in both studies were present at the start of the studies and did not represent newly incident tumors detected by regular screening.^3,5

Both of these trials would be improved if they started with cohorts known to be disease-free at baseline. Additionally, the Shanghai study randomized patients in clusters. The only English-language report of this study did not describe whether adjustments for this were made in analysis;⁵ failing to do so could overestimate the benefit of screening.

Recommendations from others

The American Association for the Study of Liver Disease recommends that carriers of the hepatitis B virus who are at high risk for developing hepatocellular carcinoma—men aged >45 years, those with cirrhosis or a family history of hepatocellular carcinoma—should be screened periodically with AFP/US. Also consider periodic screening for low-risk HBsAg+ patients who are from an area where hepatocellular carcinoma is endemic (SOR: C, based on expert opinion or descriptive epidemiology).⁶

Evidence summary

Many serum markers and screening methods have been proposed to detect hepatocellular carcinoma at a treatable stage, but only 2—AFP and US—are in clinical use.¹

A Cochrane systematic review on screening for hepatocellular carcinoma in the HBsAg+ population was published in 2003 and updated May 2004.² Our literature search did not find any subsequent relevant trials. The Cochrane review included 2 randomized control trials. The larger trial was performed in Shanghai, China and included 18,816 HBsAg+ patients aged 35 to 55 years.³ Subjects were recruited from their place of employment and randomized to either AFP/US every 6 months (n=9373) or to no screening (n=9443).

Fifty-one hepatocellular carcinomas were diagnosed in the control group and 86 in screened group. Screened subjects had a significantly higher percentage of tumors that were less than 5 cm at the time of diagnosis and a higher number of patients who underwent resection. While the 5-year survival for those with hepatocellular carcinoma in the screened group was higher, the disease-specific mortality rate was not statistically different between the 2 groups.

Additional data became available in 2002. The original study authors claimed the new data showed a statistically significant disease-specific mortality rate ratio of 0.63, favoring the screened group.⁴ However, the Cochrane group performed their own analysis on the same data and determined that no statistically significant difference in the disease-specific mortality rates existed between the 2 groups.² Therefore, it is not clear whether these new data definitively demonstrate that screening provides any benefit.

The other randomized control trial took place in Toronto, and included 1069 patients, 71% of whom were of Asian ancestry. Subjects had AFP testing every 6 months, and half were randomly assigned to have US performed every 6 months.⁵ Eight of the 11 incident tumors would have been diagnosed based on AFP levels alone, and 3 would have been missed with US alone. The authors conclude that for AFP, sensitivity=64.3% and specificity=91.4%; for US, sensitivity=78.8% and specificity=93.8%. However, their study was too small to determine if AFP/US is superior to AFP for hepatocellular carcinoma screening in a HBsAg+ population. They estimate that detecting such a difference would take a sample size of 10,000 or more.

Both studies have important flaws. Neither study applied a reference standard test (such as a computed tomography scan or magnetic resonance imaging) to both study arms. Carcinomas may have been undetected by either AFP or US. Without knowing the real prevalence of hepatocellular carcinoma, the true sensitivity and specificity for AFP, US, and AFP/US in these studies cannot be determined. Both studies included prevalent tumors (tumors diagnosed during the very first screening cycle) in their analysis. Approximately 20% of detected carcinomas in both studies were present at the start of the studies and did not represent newly incident tumors detected by regular screening.^3,5

Both of these trials would be improved if they started with cohorts known to be disease-free at baseline. Additionally, the Shanghai study randomized patients in clusters. The only English-language report of this study did not describe whether adjustments for this were made in analysis;⁵ failing to do so could overestimate the benefit of screening.

Recommendations from others

The American Association for the Study of Liver Disease recommends that carriers of the hepatitis B virus who are at high risk for developing hepatocellular carcinoma—men aged >45 years, those with cirrhosis or a family history of hepatocellular carcinoma—should be screened periodically with AFP/US. Also consider periodic screening for low-risk HBsAg+ patients who are from an area where hepatocellular carcinoma is endemic (SOR: C, based on expert opinion or descriptive epidemiology).⁶

Evidence summary

Many serum markers and screening methods have been proposed to detect hepatocellular carcinoma at a treatable stage, but only 2—AFP and US—are in clinical use.¹

A Cochrane systematic review on screening for hepatocellular carcinoma in the HBsAg+ population was published in 2003 and updated May 2004.² Our literature search did not find any subsequent relevant trials. The Cochrane review included 2 randomized control trials. The larger trial was performed in Shanghai, China and included 18,816 HBsAg+ patients aged 35 to 55 years.³ Subjects were recruited from their place of employment and randomized to either AFP/US every 6 months (n=9373) or to no screening (n=9443).

Fifty-one hepatocellular carcinomas were diagnosed in the control group and 86 in screened group. Screened subjects had a significantly higher percentage of tumors that were less than 5 cm at the time of diagnosis and a higher number of patients who underwent resection. While the 5-year survival for those with hepatocellular carcinoma in the screened group was higher, the disease-specific mortality rate was not statistically different between the 2 groups.

Additional data became available in 2002. The original study authors claimed the new data showed a statistically significant disease-specific mortality rate ratio of 0.63, favoring the screened group.⁴ However, the Cochrane group performed their own analysis on the same data and determined that no statistically significant difference in the disease-specific mortality rates existed between the 2 groups.² Therefore, it is not clear whether these new data definitively demonstrate that screening provides any benefit.

The other randomized control trial took place in Toronto, and included 1069 patients, 71% of whom were of Asian ancestry. Subjects had AFP testing every 6 months, and half were randomly assigned to have US performed every 6 months.⁵ Eight of the 11 incident tumors would have been diagnosed based on AFP levels alone, and 3 would have been missed with US alone. The authors conclude that for AFP, sensitivity=64.3% and specificity=91.4%; for US, sensitivity=78.8% and specificity=93.8%. However, their study was too small to determine if AFP/US is superior to AFP for hepatocellular carcinoma screening in a HBsAg+ population. They estimate that detecting such a difference would take a sample size of 10,000 or more.

Both studies have important flaws. Neither study applied a reference standard test (such as a computed tomography scan or magnetic resonance imaging) to both study arms. Carcinomas may have been undetected by either AFP or US. Without knowing the real prevalence of hepatocellular carcinoma, the true sensitivity and specificity for AFP, US, and AFP/US in these studies cannot be determined. Both studies included prevalent tumors (tumors diagnosed during the very first screening cycle) in their analysis. Approximately 20% of detected carcinomas in both studies were present at the start of the studies and did not represent newly incident tumors detected by regular screening.^3,5

Both of these trials would be improved if they started with cohorts known to be disease-free at baseline. Additionally, the Shanghai study randomized patients in clusters. The only English-language report of this study did not describe whether adjustments for this were made in analysis;⁵ failing to do so could overestimate the benefit of screening.

Recommendations from others

The American Association for the Study of Liver Disease recommends that carriers of the hepatitis B virus who are at high risk for developing hepatocellular carcinoma—men aged >45 years, those with cirrhosis or a family history of hepatocellular carcinoma—should be screened periodically with AFP/US. Also consider periodic screening for low-risk HBsAg+ patients who are from an area where hepatocellular carcinoma is endemic (SOR: C, based on expert opinion or descriptive epidemiology).⁶

Evidence summary

Contrary to the goals of Healthy People 2010, the rate of cesarean sections is increasing.¹ The repeat cesarean rate for low-risk women of all ages and racial groups is now 88.7%, the highest rate since the Centers for Disease Control and Prevention (CDC) began tracking the statistic in 1989. Is VBAC safe, or is a trial of labor no longer supported by the data?

The most recent Cochrane Review found that both VBAC and repeat lowtransverse cesarean section have benefits and risks associated with them; however, after reviewing the limited data, they concluded that no trial exists to adequately help women and their caregivers make an informed decision between the two.² A strong theme in the Cochrane Review, echoed in most reviews, was the absence of high-quality prospective randomized data.

In an attempt to quantify the risks of VBAC, a systematic review determined that attempted VBAC, compared with repeat low-transverse cesarean section, increased the risk of uterine rupture by 2.7 per 1000 cases (95% confidence interval [CI], 0.73–4.73).³ This additional risk rate is often quoted in VBAC reviews and was cited in the Agency for Healthcare Research and Quality evidence report; it is based on 1 prospective, nonrandomized cohort trial and 1 retrospective cohort study.^4,5

No randomized controlled trials exist for determining maternal safety of VBAC, although another recent systematic review found 2 nonrandomized prospective trials of sufficient quality to analyze. The authors concluded there were “no statistically significant differences between planned elective repeat cesarean section and planned VBAC.”⁶ Upon closer review in PubMed, one of the cited studies did not study 312 patients for VBAC outcomes as alleged; rather, it investigated patient attitudes towards VBAC.⁷

Since publication of that review, a large, multicenter, prospective, nonrandomized trial involving 33,699 patients found no significant difference between VBAC and planned cesarean for hysterectomy (0.2% vs 0.3%; odds ratio [OR]=0.77; 95% CI, 0.51–1.17), maternal death (0.02% vs 0.04%; OR=0.38; 95% CI, 0.1–1.46), and neonatal death (0.08% vs 0.05%; OR=1.82; 95% CI, 0.73–4.57).⁸ Significant associations were found for uterine rupture rates in spontaneous labor (24/6685 [0.4%] vs no cases; number needed to harm [NNH]=279) and neonatal hypoxic-ischemic encephalopathy (0.46 cases per 1000 vs no cases; NNH=2174).⁸

A retrospective Canadian cohort trial of 308,755 women also demonstrated an association of VBAC with uterine rupture(0.65% of trial-of-labor cases; OR=2.38; 95% CI, 2.12–2.67), and a trend towards higher maternal mortality in the cesarean group (1.6 per 100,000 for VBAC vs 5.6 per 100,000 for planned cesarean; OR=0.32; 95% CI, 0.07–1.47).⁹

The effect of VBAC on neonatal morbidity and mortality is unclear. In contrast to the negative larger trial,⁸ a smaller retrospective cohort of 24,529 births found a higher association of perinatal death for trial of labor (adjusted OR=11.7; 95% CI, 1.4–101.6).¹⁰ The perinatal death rate was similar to rates in nulliparous women. Regarding morbidity, one retrospective cohort trial showed VBAC was associated with an increase in neonatal sepsis (1% vs 0%; CI not given) compared with planned cesarean, but VBAC resulted in less transient tachypnea (5% vs 7%) and hyper-bilirubinemia (2% vs 6%).¹¹

Recommendations from others

Both the American College of Obstetricians and Gynecologists and the Society of Obstetricians and Gynecologists of Canada state that women with 1 previous low-transverse cesarean section should be offered a trial of labor after appropriate counseling of the risks and benefits.^12,13 Furthermore, induction with oxytocin is allowed, but the use of prostaglandins is not recommended. Based on expert opinion, both organizations encourage VBAC only in institutions staffed with surgeons and anesthesiologists immediately available to provide emergent cesarean.

Acknowledgments

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

Evidence summary

Contrary to the goals of Healthy People 2010, the rate of cesarean sections is increasing.¹ The repeat cesarean rate for low-risk women of all ages and racial groups is now 88.7%, the highest rate since the Centers for Disease Control and Prevention (CDC) began tracking the statistic in 1989. Is VBAC safe, or is a trial of labor no longer supported by the data?

The most recent Cochrane Review found that both VBAC and repeat lowtransverse cesarean section have benefits and risks associated with them; however, after reviewing the limited data, they concluded that no trial exists to adequately help women and their caregivers make an informed decision between the two.² A strong theme in the Cochrane Review, echoed in most reviews, was the absence of high-quality prospective randomized data.

In an attempt to quantify the risks of VBAC, a systematic review determined that attempted VBAC, compared with repeat low-transverse cesarean section, increased the risk of uterine rupture by 2.7 per 1000 cases (95% confidence interval [CI], 0.73–4.73).³ This additional risk rate is often quoted in VBAC reviews and was cited in the Agency for Healthcare Research and Quality evidence report; it is based on 1 prospective, nonrandomized cohort trial and 1 retrospective cohort study.^4,5

No randomized controlled trials exist for determining maternal safety of VBAC, although another recent systematic review found 2 nonrandomized prospective trials of sufficient quality to analyze. The authors concluded there were “no statistically significant differences between planned elective repeat cesarean section and planned VBAC.”⁶ Upon closer review in PubMed, one of the cited studies did not study 312 patients for VBAC outcomes as alleged; rather, it investigated patient attitudes towards VBAC.⁷

Since publication of that review, a large, multicenter, prospective, nonrandomized trial involving 33,699 patients found no significant difference between VBAC and planned cesarean for hysterectomy (0.2% vs 0.3%; odds ratio [OR]=0.77; 95% CI, 0.51–1.17), maternal death (0.02% vs 0.04%; OR=0.38; 95% CI, 0.1–1.46), and neonatal death (0.08% vs 0.05%; OR=1.82; 95% CI, 0.73–4.57).⁸ Significant associations were found for uterine rupture rates in spontaneous labor (24/6685 [0.4%] vs no cases; number needed to harm [NNH]=279) and neonatal hypoxic-ischemic encephalopathy (0.46 cases per 1000 vs no cases; NNH=2174).⁸

A retrospective Canadian cohort trial of 308,755 women also demonstrated an association of VBAC with uterine rupture(0.65% of trial-of-labor cases; OR=2.38; 95% CI, 2.12–2.67), and a trend towards higher maternal mortality in the cesarean group (1.6 per 100,000 for VBAC vs 5.6 per 100,000 for planned cesarean; OR=0.32; 95% CI, 0.07–1.47).⁹

The effect of VBAC on neonatal morbidity and mortality is unclear. In contrast to the negative larger trial,⁸ a smaller retrospective cohort of 24,529 births found a higher association of perinatal death for trial of labor (adjusted OR=11.7; 95% CI, 1.4–101.6).¹⁰ The perinatal death rate was similar to rates in nulliparous women. Regarding morbidity, one retrospective cohort trial showed VBAC was associated with an increase in neonatal sepsis (1% vs 0%; CI not given) compared with planned cesarean, but VBAC resulted in less transient tachypnea (5% vs 7%) and hyper-bilirubinemia (2% vs 6%).¹¹

Recommendations from others

Both the American College of Obstetricians and Gynecologists and the Society of Obstetricians and Gynecologists of Canada state that women with 1 previous low-transverse cesarean section should be offered a trial of labor after appropriate counseling of the risks and benefits.^12,13 Furthermore, induction with oxytocin is allowed, but the use of prostaglandins is not recommended. Based on expert opinion, both organizations encourage VBAC only in institutions staffed with surgeons and anesthesiologists immediately available to provide emergent cesarean.

Acknowledgments

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

Evidence summary

Contrary to the goals of Healthy People 2010, the rate of cesarean sections is increasing.¹ The repeat cesarean rate for low-risk women of all ages and racial groups is now 88.7%, the highest rate since the Centers for Disease Control and Prevention (CDC) began tracking the statistic in 1989. Is VBAC safe, or is a trial of labor no longer supported by the data?

The most recent Cochrane Review found that both VBAC and repeat lowtransverse cesarean section have benefits and risks associated with them; however, after reviewing the limited data, they concluded that no trial exists to adequately help women and their caregivers make an informed decision between the two.² A strong theme in the Cochrane Review, echoed in most reviews, was the absence of high-quality prospective randomized data.

In an attempt to quantify the risks of VBAC, a systematic review determined that attempted VBAC, compared with repeat low-transverse cesarean section, increased the risk of uterine rupture by 2.7 per 1000 cases (95% confidence interval [CI], 0.73–4.73).³ This additional risk rate is often quoted in VBAC reviews and was cited in the Agency for Healthcare Research and Quality evidence report; it is based on 1 prospective, nonrandomized cohort trial and 1 retrospective cohort study.^4,5

No randomized controlled trials exist for determining maternal safety of VBAC, although another recent systematic review found 2 nonrandomized prospective trials of sufficient quality to analyze. The authors concluded there were “no statistically significant differences between planned elective repeat cesarean section and planned VBAC.”⁶ Upon closer review in PubMed, one of the cited studies did not study 312 patients for VBAC outcomes as alleged; rather, it investigated patient attitudes towards VBAC.⁷

Since publication of that review, a large, multicenter, prospective, nonrandomized trial involving 33,699 patients found no significant difference between VBAC and planned cesarean for hysterectomy (0.2% vs 0.3%; odds ratio [OR]=0.77; 95% CI, 0.51–1.17), maternal death (0.02% vs 0.04%; OR=0.38; 95% CI, 0.1–1.46), and neonatal death (0.08% vs 0.05%; OR=1.82; 95% CI, 0.73–4.57).⁸ Significant associations were found for uterine rupture rates in spontaneous labor (24/6685 [0.4%] vs no cases; number needed to harm [NNH]=279) and neonatal hypoxic-ischemic encephalopathy (0.46 cases per 1000 vs no cases; NNH=2174).⁸

A retrospective Canadian cohort trial of 308,755 women also demonstrated an association of VBAC with uterine rupture(0.65% of trial-of-labor cases; OR=2.38; 95% CI, 2.12–2.67), and a trend towards higher maternal mortality in the cesarean group (1.6 per 100,000 for VBAC vs 5.6 per 100,000 for planned cesarean; OR=0.32; 95% CI, 0.07–1.47).⁹

The effect of VBAC on neonatal morbidity and mortality is unclear. In contrast to the negative larger trial,⁸ a smaller retrospective cohort of 24,529 births found a higher association of perinatal death for trial of labor (adjusted OR=11.7; 95% CI, 1.4–101.6).¹⁰ The perinatal death rate was similar to rates in nulliparous women. Regarding morbidity, one retrospective cohort trial showed VBAC was associated with an increase in neonatal sepsis (1% vs 0%; CI not given) compared with planned cesarean, but VBAC resulted in less transient tachypnea (5% vs 7%) and hyper-bilirubinemia (2% vs 6%).¹¹

Recommendations from others

Both the American College of Obstetricians and Gynecologists and the Society of Obstetricians and Gynecologists of Canada state that women with 1 previous low-transverse cesarean section should be offered a trial of labor after appropriate counseling of the risks and benefits.^12,13 Furthermore, induction with oxytocin is allowed, but the use of prostaglandins is not recommended. Based on expert opinion, both organizations encourage VBAC only in institutions staffed with surgeons and anesthesiologists immediately available to provide emergent cesarean.

Acknowledgments

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

Evidence summary

One study was found that attempted to determine the appropriate follow-up for women diagnosed with CIN1 on adequate colposcopic biopsy (FIGURE). This 2-year prospective study examined a subpopulation of 1539 women from the ASCUS/LSIL (atypical squamous cells of uncertain significance)/low-grade squamous intraepithelial lesion) Triage Study (ALTS) to determine the ideal follow-up strategy for women diagnosed with CIN1 or HPV effect on colposcopic biopsy-obtained histology. This study randomly assigned these women with CIN1 or HPV effect to either HPV testing or colposcopic examination at 6, 12, and 18 months. Every woman under-went an exit colposcopy at 24 months.

The study found that hr-HPV testing 12 months after the initial colposcopic exam had the highest sensitivity for detecting advanced disease (92.2%) and lowest referral rate to repeat colposcopy (55%). Follow-up of these patients with repeat cytology alone at 6 and 12 months had a lower sensitivity for detection of advanced disease (85%) and greater referral rate to repeat colposcopy (60%) when compared with HPV testing at 12 months alone. Three cytologic evaluations at 6, 12, and 18 months without HPV testing increased sensitivity (95%), although this increase was not statistically significant. A much higher percentage of patients were referred to colposcopy with this strategy. Combining both hr-HPV testing and cytology at 12 months did not significantly increase the identification of advanced disease and resulted in a higher re-referral rate to colposcopy.^1-3

TABLE
Strategies for managing CIN1

Recommendations from others

American Society for Colposcopy and Cervical Pathology consensus guidelines for the management of women with CIN were published in 2003. Their recommendation now states that follow-up after adequate colposcopy with a biopsy revealing CIN1 or HPV effect may include either repeat cervical cytology tests at 6 and 12 months or HPV testing at 12 months. After a negative test for high-risk HPV types or 2 consecutive negative cervical cytology tests, the patient may return to annual cytologic screening. If the HPV test is positive for high-risk viral types or the cytology is reported as atypical squamous cells (ASC) or higher, the patient should undergo repeat colposcopy.⁴

Evidence summary

One study was found that attempted to determine the appropriate follow-up for women diagnosed with CIN1 on adequate colposcopic biopsy (FIGURE). This 2-year prospective study examined a subpopulation of 1539 women from the ASCUS/LSIL (atypical squamous cells of uncertain significance)/low-grade squamous intraepithelial lesion) Triage Study (ALTS) to determine the ideal follow-up strategy for women diagnosed with CIN1 or HPV effect on colposcopic biopsy-obtained histology. This study randomly assigned these women with CIN1 or HPV effect to either HPV testing or colposcopic examination at 6, 12, and 18 months. Every woman under-went an exit colposcopy at 24 months.

The study found that hr-HPV testing 12 months after the initial colposcopic exam had the highest sensitivity for detecting advanced disease (92.2%) and lowest referral rate to repeat colposcopy (55%). Follow-up of these patients with repeat cytology alone at 6 and 12 months had a lower sensitivity for detection of advanced disease (85%) and greater referral rate to repeat colposcopy (60%) when compared with HPV testing at 12 months alone. Three cytologic evaluations at 6, 12, and 18 months without HPV testing increased sensitivity (95%), although this increase was not statistically significant. A much higher percentage of patients were referred to colposcopy with this strategy. Combining both hr-HPV testing and cytology at 12 months did not significantly increase the identification of advanced disease and resulted in a higher re-referral rate to colposcopy.^1-3

TABLE
Strategies for managing CIN1

Recommendations from others

American Society for Colposcopy and Cervical Pathology consensus guidelines for the management of women with CIN were published in 2003. Their recommendation now states that follow-up after adequate colposcopy with a biopsy revealing CIN1 or HPV effect may include either repeat cervical cytology tests at 6 and 12 months or HPV testing at 12 months. After a negative test for high-risk HPV types or 2 consecutive negative cervical cytology tests, the patient may return to annual cytologic screening. If the HPV test is positive for high-risk viral types or the cytology is reported as atypical squamous cells (ASC) or higher, the patient should undergo repeat colposcopy.⁴

Evidence summary

One study was found that attempted to determine the appropriate follow-up for women diagnosed with CIN1 on adequate colposcopic biopsy (FIGURE). This 2-year prospective study examined a subpopulation of 1539 women from the ASCUS/LSIL (atypical squamous cells of uncertain significance)/low-grade squamous intraepithelial lesion) Triage Study (ALTS) to determine the ideal follow-up strategy for women diagnosed with CIN1 or HPV effect on colposcopic biopsy-obtained histology. This study randomly assigned these women with CIN1 or HPV effect to either HPV testing or colposcopic examination at 6, 12, and 18 months. Every woman under-went an exit colposcopy at 24 months.

The study found that hr-HPV testing 12 months after the initial colposcopic exam had the highest sensitivity for detecting advanced disease (92.2%) and lowest referral rate to repeat colposcopy (55%). Follow-up of these patients with repeat cytology alone at 6 and 12 months had a lower sensitivity for detection of advanced disease (85%) and greater referral rate to repeat colposcopy (60%) when compared with HPV testing at 12 months alone. Three cytologic evaluations at 6, 12, and 18 months without HPV testing increased sensitivity (95%), although this increase was not statistically significant. A much higher percentage of patients were referred to colposcopy with this strategy. Combining both hr-HPV testing and cytology at 12 months did not significantly increase the identification of advanced disease and resulted in a higher re-referral rate to colposcopy.^1-3

TABLE
Strategies for managing CIN1

Recommendations from others

American Society for Colposcopy and Cervical Pathology consensus guidelines for the management of women with CIN were published in 2003. Their recommendation now states that follow-up after adequate colposcopy with a biopsy revealing CIN1 or HPV effect may include either repeat cervical cytology tests at 6 and 12 months or HPV testing at 12 months. After a negative test for high-risk HPV types or 2 consecutive negative cervical cytology tests, the patient may return to annual cytologic screening. If the HPV test is positive for high-risk viral types or the cytology is reported as atypical squamous cells (ASC) or higher, the patient should undergo repeat colposcopy.⁴

Evidence summary

Hydroxymethyl glutaryl coenzyme A (HMG CoA) reductase inhibitors, commonly called statins, have been on the market since the late 1980s. Statins are primarily used to treat hypercholesterolemia, and in recent years have been shown to reduce the risks of coronary events, stroke, and cardiovascular mortality.¹

Use of statins is contraindicated during pregnancy based on pre-marketing animal studies showing developmental toxicities in animal fetuses; consequently they are pregnancy category X.² To date, no controlled studies demonstrate teratogenic effects in humans; however, numerous case reports have documented congenital anomalies, including vertebral, anal, cardiac, tracheal, esophageal, renal, and limb deficiency (VACTERL association), intrauterine growth retardation (IUGR), and demise in fetuses exposed during pregnancy, especially in the first trimester. It is thought that adverse events are under-reported and likely biased toward severe outcomes, thereby limiting actual reported exposures. Despite this limitation, the likelihood of observing specific anomalies has been predicted based upon prescription data and birth rates. The overall birth prevalence of any isolated lower-limb defect or VACTERL anomaly is estimated as 1:100,000 and ranges from 1:50,000 for simvastatin (Zocor) to 1:500,000 for lovastatin (Mevacor).³ These congenital anomaly frequencies do not exceed general population rates.

One study suggests that short-term use of simvastatin does not affect menstruation or ovulation of premenopausal women. This double-blind, randomized, placebo-controlled trial enrolled 86 normally cycling women. Mean age of women completing the study was 35. Simvastatin 40 mg/d was studied for cholesterol effects and female reproductive effects. Urinary luteinizing hormone (LH) and pregnanediol glucuronide (PDG), a progesterone metabolite, were assessed to determine if treatment with simvastatin adversely affects luteal function. Simvastatin lowered low-density lipoprotein (LDL) cholesterol by 34.3% (P<.001). Normal luteal phase duration and peak were confirmed by urinary PDG and LH levels. This study demonstrated that treatment with simvastatin for 4 months had no significant clinical changes on reproductive gonadal function compared with placebo.⁴

Although ovulation may not be affected by simvastatin, do statins provide a reward worth the risk of other adverse effects? A recent meta-analysis evaluated the benefits of lipid-lowering medication in trials of at least 1 year duration that included women. Total and coronary heart disease (CHD) mortality, nonfatal myocardial infarction, revascularization, and total CHD events were assessed among women with and without cardiovascular disease (CVD). Ten trials included statins. Of the 5 studies that reported age, the average was 61 years. For women without CVD, lipid-lowering treatment was not shown to affect total or CHD mortality. For women with known CVD, hyperlipidemia treatment did not affect total mortality, but was shown effective in reducing CHD events, CHD mortality, nonfatal myocardial infarction, and revascularization; the relative risk of CHD events for statin users was 0.80 (95% confidence interval [CI], 0.71–0.91). The number of women needed to treat (NNT) to prevent an initial CHD event was 140. For secondary prevention, the NNT to prevent 1 CHD event was 26. Since women of child-bearing potential have lower probability of CHD events compared to the older women studied in this meta-analysis, the expected benefit for younger women is likely to be substantially lower.⁵

Consider initial pregnancy tests and inform all women of childbearing age of the possibility of fetal injury before starting statin therapy.² Highly lipophilic statins—such as simvastatin, atorvastatin (Lipitor), and lovastatin—achieve embryoplacental concentrations similar to those of maternal plasma. For this reason, if statin therapy is needed, these agents should be avoided. Pravastatin (Pravachol) is the most hydrophilic statin and has no reports of abnormal pregnancy outcomes, even in animal research.³

Recommendations from others

The National Cholesterol Education Program Expert Panel and the American Heart Association make no specific recommendations regarding precautions with statin use for women of childbearing age who require treatment for hypercholesterolemia or coronary heart disease.^6,7 The American College of Obstetrics and Gynecologists makes no distinction regarding recommendations for pharmacological treatment of hyperlipidemia for women aged 20 to 45 years.⁸

The US Preventive Services Task Force makes no recommendations on treatment with statins; they only address screening for hypercholesterolemia.⁹ The Food and Drug Administration has given statin agents a pregnancy category of X (risks involved in use of the drug by pregnant women clearly outweigh potential benefits).

Evidence summary

Hydroxymethyl glutaryl coenzyme A (HMG CoA) reductase inhibitors, commonly called statins, have been on the market since the late 1980s. Statins are primarily used to treat hypercholesterolemia, and in recent years have been shown to reduce the risks of coronary events, stroke, and cardiovascular mortality.¹

Use of statins is contraindicated during pregnancy based on pre-marketing animal studies showing developmental toxicities in animal fetuses; consequently they are pregnancy category X.² To date, no controlled studies demonstrate teratogenic effects in humans; however, numerous case reports have documented congenital anomalies, including vertebral, anal, cardiac, tracheal, esophageal, renal, and limb deficiency (VACTERL association), intrauterine growth retardation (IUGR), and demise in fetuses exposed during pregnancy, especially in the first trimester. It is thought that adverse events are under-reported and likely biased toward severe outcomes, thereby limiting actual reported exposures. Despite this limitation, the likelihood of observing specific anomalies has been predicted based upon prescription data and birth rates. The overall birth prevalence of any isolated lower-limb defect or VACTERL anomaly is estimated as 1:100,000 and ranges from 1:50,000 for simvastatin (Zocor) to 1:500,000 for lovastatin (Mevacor).³ These congenital anomaly frequencies do not exceed general population rates.

One study suggests that short-term use of simvastatin does not affect menstruation or ovulation of premenopausal women. This double-blind, randomized, placebo-controlled trial enrolled 86 normally cycling women. Mean age of women completing the study was 35. Simvastatin 40 mg/d was studied for cholesterol effects and female reproductive effects. Urinary luteinizing hormone (LH) and pregnanediol glucuronide (PDG), a progesterone metabolite, were assessed to determine if treatment with simvastatin adversely affects luteal function. Simvastatin lowered low-density lipoprotein (LDL) cholesterol by 34.3% (P<.001). Normal luteal phase duration and peak were confirmed by urinary PDG and LH levels. This study demonstrated that treatment with simvastatin for 4 months had no significant clinical changes on reproductive gonadal function compared with placebo.⁴

Although ovulation may not be affected by simvastatin, do statins provide a reward worth the risk of other adverse effects? A recent meta-analysis evaluated the benefits of lipid-lowering medication in trials of at least 1 year duration that included women. Total and coronary heart disease (CHD) mortality, nonfatal myocardial infarction, revascularization, and total CHD events were assessed among women with and without cardiovascular disease (CVD). Ten trials included statins. Of the 5 studies that reported age, the average was 61 years. For women without CVD, lipid-lowering treatment was not shown to affect total or CHD mortality. For women with known CVD, hyperlipidemia treatment did not affect total mortality, but was shown effective in reducing CHD events, CHD mortality, nonfatal myocardial infarction, and revascularization; the relative risk of CHD events for statin users was 0.80 (95% confidence interval [CI], 0.71–0.91). The number of women needed to treat (NNT) to prevent an initial CHD event was 140. For secondary prevention, the NNT to prevent 1 CHD event was 26. Since women of child-bearing potential have lower probability of CHD events compared to the older women studied in this meta-analysis, the expected benefit for younger women is likely to be substantially lower.⁵

Consider initial pregnancy tests and inform all women of childbearing age of the possibility of fetal injury before starting statin therapy.² Highly lipophilic statins—such as simvastatin, atorvastatin (Lipitor), and lovastatin—achieve embryoplacental concentrations similar to those of maternal plasma. For this reason, if statin therapy is needed, these agents should be avoided. Pravastatin (Pravachol) is the most hydrophilic statin and has no reports of abnormal pregnancy outcomes, even in animal research.³

Recommendations from others

The National Cholesterol Education Program Expert Panel and the American Heart Association make no specific recommendations regarding precautions with statin use for women of childbearing age who require treatment for hypercholesterolemia or coronary heart disease.^6,7 The American College of Obstetrics and Gynecologists makes no distinction regarding recommendations for pharmacological treatment of hyperlipidemia for women aged 20 to 45 years.⁸

The US Preventive Services Task Force makes no recommendations on treatment with statins; they only address screening for hypercholesterolemia.⁹ The Food and Drug Administration has given statin agents a pregnancy category of X (risks involved in use of the drug by pregnant women clearly outweigh potential benefits).

Evidence summary

Hydroxymethyl glutaryl coenzyme A (HMG CoA) reductase inhibitors, commonly called statins, have been on the market since the late 1980s. Statins are primarily used to treat hypercholesterolemia, and in recent years have been shown to reduce the risks of coronary events, stroke, and cardiovascular mortality.¹

Use of statins is contraindicated during pregnancy based on pre-marketing animal studies showing developmental toxicities in animal fetuses; consequently they are pregnancy category X.² To date, no controlled studies demonstrate teratogenic effects in humans; however, numerous case reports have documented congenital anomalies, including vertebral, anal, cardiac, tracheal, esophageal, renal, and limb deficiency (VACTERL association), intrauterine growth retardation (IUGR), and demise in fetuses exposed during pregnancy, especially in the first trimester. It is thought that adverse events are under-reported and likely biased toward severe outcomes, thereby limiting actual reported exposures. Despite this limitation, the likelihood of observing specific anomalies has been predicted based upon prescription data and birth rates. The overall birth prevalence of any isolated lower-limb defect or VACTERL anomaly is estimated as 1:100,000 and ranges from 1:50,000 for simvastatin (Zocor) to 1:500,000 for lovastatin (Mevacor).³ These congenital anomaly frequencies do not exceed general population rates.

One study suggests that short-term use of simvastatin does not affect menstruation or ovulation of premenopausal women. This double-blind, randomized, placebo-controlled trial enrolled 86 normally cycling women. Mean age of women completing the study was 35. Simvastatin 40 mg/d was studied for cholesterol effects and female reproductive effects. Urinary luteinizing hormone (LH) and pregnanediol glucuronide (PDG), a progesterone metabolite, were assessed to determine if treatment with simvastatin adversely affects luteal function. Simvastatin lowered low-density lipoprotein (LDL) cholesterol by 34.3% (P<.001). Normal luteal phase duration and peak were confirmed by urinary PDG and LH levels. This study demonstrated that treatment with simvastatin for 4 months had no significant clinical changes on reproductive gonadal function compared with placebo.⁴

Although ovulation may not be affected by simvastatin, do statins provide a reward worth the risk of other adverse effects? A recent meta-analysis evaluated the benefits of lipid-lowering medication in trials of at least 1 year duration that included women. Total and coronary heart disease (CHD) mortality, nonfatal myocardial infarction, revascularization, and total CHD events were assessed among women with and without cardiovascular disease (CVD). Ten trials included statins. Of the 5 studies that reported age, the average was 61 years. For women without CVD, lipid-lowering treatment was not shown to affect total or CHD mortality. For women with known CVD, hyperlipidemia treatment did not affect total mortality, but was shown effective in reducing CHD events, CHD mortality, nonfatal myocardial infarction, and revascularization; the relative risk of CHD events for statin users was 0.80 (95% confidence interval [CI], 0.71–0.91). The number of women needed to treat (NNT) to prevent an initial CHD event was 140. For secondary prevention, the NNT to prevent 1 CHD event was 26. Since women of child-bearing potential have lower probability of CHD events compared to the older women studied in this meta-analysis, the expected benefit for younger women is likely to be substantially lower.⁵

Consider initial pregnancy tests and inform all women of childbearing age of the possibility of fetal injury before starting statin therapy.² Highly lipophilic statins—such as simvastatin, atorvastatin (Lipitor), and lovastatin—achieve embryoplacental concentrations similar to those of maternal plasma. For this reason, if statin therapy is needed, these agents should be avoided. Pravastatin (Pravachol) is the most hydrophilic statin and has no reports of abnormal pregnancy outcomes, even in animal research.³

Recommendations from others

The National Cholesterol Education Program Expert Panel and the American Heart Association make no specific recommendations regarding precautions with statin use for women of childbearing age who require treatment for hypercholesterolemia or coronary heart disease.^6,7 The American College of Obstetrics and Gynecologists makes no distinction regarding recommendations for pharmacological treatment of hyperlipidemia for women aged 20 to 45 years.⁸

The US Preventive Services Task Force makes no recommendations on treatment with statins; they only address screening for hypercholesterolemia.⁹ The Food and Drug Administration has given statin agents a pregnancy category of X (risks involved in use of the drug by pregnant women clearly outweigh potential benefits).

Evidence summary

Lifestyle changes are advocated as first-line therapy for hypertension. This review examines the evidence on exercise, dietary interventions, weight loss, alcohol moderation, and smoking cessation. Average systolic blood pressure (SBP) and diastolic blood pressure (DBP) changes are reported in the TABLE.

Exercise. A well-done systematic review and meta-analysis from 2002 (including 15 studies with 770 participants) concluded that for hypertensive patients, aerobic exercise with at least one 40-minute session of moderate intensity per week is associated with a drop in SBP of about 5 mm Hg and a drop in DBP of about 4 mm Hg.¹

DASH diet. The Dietary Approaches to Stop Hypertension (DASH) diet is a diet rich in fish, chicken, lean meat, low-fat dairy, fruits, vegetables, whole grains, legumes, nuts, and seeds. In a high-quality RCT, the DASH diet lowered SBP for hypertensive patients by an average of 11 mm Hg and DBP by an average of 5.5 mm Hg compared with the control group.² Participants were provided with all food during the entire 8-week length of the trial.

Weight loss. A Cochrane review of 18 trials with 2611 participants concluded that for overweight hypertensive patients, weight loss of 3% to 9% of body weight is associated with 3 mm Hg decreases in both SBP and DBP.³

Salt reduction. A Cochrane review of 17 trials with 734 participants concluded that for individuals with hypertension, a reduced-salt diet results in a mean SBP and DBP reductions of 5 mm Hg and 3 mm Hg, respectively.⁴

Alcohol moderation. A well-done meta-analysis of alcohol reduction and blood pressure included 7 studies with 415 hypertensive patients.⁵ Mean baseline alcohol consumption was 3 to 6 alcoholic drinks per day, and the mean reduction in consumption was 67%. For this patient population, the average improvement was almost 4 mm Hg for SBP and nearly 2.5 mm Hg for DBP.

Smoking cessation. No high-quality studies show a long-term effect of smoking cessation on blood pressure. Smoking cessation has other well-documented health benefits and should still be recommended for patients with hypertension.

Multifactorial interventions. Thirteen randomized controlled trials of community-based interventions involving various combinations of lifestyle change advice show mixed results. In general, studies of interventions that were more intensive (ie, longer in duration, larger number of sessions, small group or one-on-one as opposed to large group lectures) and studies with shorter follow-up periods showed more positive results. The magnitude of the blood pressure improvements tended to be lower than for each individual intervention described above. (References are located in the APPENDIX on our web site at www.jfponline.com.

TABLE
Average effect on blood pressure from lifestyle interventions

Recommendations from others

The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure recommends lifestyle modifications for all patients with hypertension.⁶ They point out that DASH diet plan with 1600 mg sodium had average blood pressure effects similar to single-drug therapy.

Evidence summary

Lifestyle changes are advocated as first-line therapy for hypertension. This review examines the evidence on exercise, dietary interventions, weight loss, alcohol moderation, and smoking cessation. Average systolic blood pressure (SBP) and diastolic blood pressure (DBP) changes are reported in the TABLE.

Exercise. A well-done systematic review and meta-analysis from 2002 (including 15 studies with 770 participants) concluded that for hypertensive patients, aerobic exercise with at least one 40-minute session of moderate intensity per week is associated with a drop in SBP of about 5 mm Hg and a drop in DBP of about 4 mm Hg.¹

DASH diet. The Dietary Approaches to Stop Hypertension (DASH) diet is a diet rich in fish, chicken, lean meat, low-fat dairy, fruits, vegetables, whole grains, legumes, nuts, and seeds. In a high-quality RCT, the DASH diet lowered SBP for hypertensive patients by an average of 11 mm Hg and DBP by an average of 5.5 mm Hg compared with the control group.² Participants were provided with all food during the entire 8-week length of the trial.

Weight loss. A Cochrane review of 18 trials with 2611 participants concluded that for overweight hypertensive patients, weight loss of 3% to 9% of body weight is associated with 3 mm Hg decreases in both SBP and DBP.³

Salt reduction. A Cochrane review of 17 trials with 734 participants concluded that for individuals with hypertension, a reduced-salt diet results in a mean SBP and DBP reductions of 5 mm Hg and 3 mm Hg, respectively.⁴

Alcohol moderation. A well-done meta-analysis of alcohol reduction and blood pressure included 7 studies with 415 hypertensive patients.⁵ Mean baseline alcohol consumption was 3 to 6 alcoholic drinks per day, and the mean reduction in consumption was 67%. For this patient population, the average improvement was almost 4 mm Hg for SBP and nearly 2.5 mm Hg for DBP.

Smoking cessation. No high-quality studies show a long-term effect of smoking cessation on blood pressure. Smoking cessation has other well-documented health benefits and should still be recommended for patients with hypertension.

Multifactorial interventions. Thirteen randomized controlled trials of community-based interventions involving various combinations of lifestyle change advice show mixed results. In general, studies of interventions that were more intensive (ie, longer in duration, larger number of sessions, small group or one-on-one as opposed to large group lectures) and studies with shorter follow-up periods showed more positive results. The magnitude of the blood pressure improvements tended to be lower than for each individual intervention described above. (References are located in the APPENDIX on our web site at www.jfponline.com.

TABLE
Average effect on blood pressure from lifestyle interventions

Recommendations from others

The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure recommends lifestyle modifications for all patients with hypertension.⁶ They point out that DASH diet plan with 1600 mg sodium had average blood pressure effects similar to single-drug therapy.

Evidence summary

Lifestyle changes are advocated as first-line therapy for hypertension. This review examines the evidence on exercise, dietary interventions, weight loss, alcohol moderation, and smoking cessation. Average systolic blood pressure (SBP) and diastolic blood pressure (DBP) changes are reported in the TABLE.

Exercise. A well-done systematic review and meta-analysis from 2002 (including 15 studies with 770 participants) concluded that for hypertensive patients, aerobic exercise with at least one 40-minute session of moderate intensity per week is associated with a drop in SBP of about 5 mm Hg and a drop in DBP of about 4 mm Hg.¹

DASH diet. The Dietary Approaches to Stop Hypertension (DASH) diet is a diet rich in fish, chicken, lean meat, low-fat dairy, fruits, vegetables, whole grains, legumes, nuts, and seeds. In a high-quality RCT, the DASH diet lowered SBP for hypertensive patients by an average of 11 mm Hg and DBP by an average of 5.5 mm Hg compared with the control group.² Participants were provided with all food during the entire 8-week length of the trial.

Weight loss. A Cochrane review of 18 trials with 2611 participants concluded that for overweight hypertensive patients, weight loss of 3% to 9% of body weight is associated with 3 mm Hg decreases in both SBP and DBP.³

Salt reduction. A Cochrane review of 17 trials with 734 participants concluded that for individuals with hypertension, a reduced-salt diet results in a mean SBP and DBP reductions of 5 mm Hg and 3 mm Hg, respectively.⁴

Alcohol moderation. A well-done meta-analysis of alcohol reduction and blood pressure included 7 studies with 415 hypertensive patients.⁵ Mean baseline alcohol consumption was 3 to 6 alcoholic drinks per day, and the mean reduction in consumption was 67%. For this patient population, the average improvement was almost 4 mm Hg for SBP and nearly 2.5 mm Hg for DBP.

Smoking cessation. No high-quality studies show a long-term effect of smoking cessation on blood pressure. Smoking cessation has other well-documented health benefits and should still be recommended for patients with hypertension.

Multifactorial interventions. Thirteen randomized controlled trials of community-based interventions involving various combinations of lifestyle change advice show mixed results. In general, studies of interventions that were more intensive (ie, longer in duration, larger number of sessions, small group or one-on-one as opposed to large group lectures) and studies with shorter follow-up periods showed more positive results. The magnitude of the blood pressure improvements tended to be lower than for each individual intervention described above. (References are located in the APPENDIX on our web site at www.jfponline.com.

TABLE
Average effect on blood pressure from lifestyle interventions

Recommendations from others

The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure recommends lifestyle modifications for all patients with hypertension.⁶ They point out that DASH diet plan with 1600 mg sodium had average blood pressure effects similar to single-drug therapy.