Clinical Review

JUDY’S CASE

“WHAT’S MY RISK?”

At her periodic gynecologic exam, Judy, a 58-year-old white woman, expresses concern about her heart health in light of her 62-year-old sister’s recent heart attack. Further questioning reveals that her father died of a heart attack at age 56, and her brother, 52, has high blood pressure and adult-onset diabetes.

Judy has not experienced any symptoms of cardiovascular disease, such as chest pain or tightness with exertion, and she doesn’t smoke. The last time her cholesterol was checked was about 15 years earlier, at which time it was “OK.” She admits she is not very physically active and has gained about 30 lb over the past 10 years. Her vital signs and physical exam are entirely normal except for borderline high blood pressure at 140/90 mm Hg, weight of 170 lb (height: 68 inches), and a waist circumference of 37 inches.

What is her cardiovascular risk?

Judy has physical findings suggestive of metabolic syndrome in addition to the significant family history of cardiovascular disease (CVD). Although her current risk of a cardiac event appears to be low, she is likely to deteriorate if the hypertension and excess body weight are not addressed.

To predict her level of risk more precisely, the physician asks Judy to return in 2 weeks for a blood pressure recheck, and instructs her to perform additional readings on her own. The clinician also refers Judy for a fasting lipid panel and blood glucose level.

In women, CVD is especially lethal

Contrary to earlier assumptions, CVD now appears to be more lethal in women than in men and warrants aggressive efforts to prevent it and manage risk factors (FIGURE). This article focuses on improving high-density lipoprotein (HDL) cholesterol, a key factor in women at risk.

This approach differs slightly from the National Cholesterol Education Program Adult Treatment Panel III (NCEP/ATP III) guidelines, which target low-density lipoprotein (LDL) cholesterol as the primary lipid risk factor for intervention.¹

FIGURE Women surpass men in CVD deaths

Over the past 25 years, the trend in deaths attributable to cardiovascular disease has been upward for women, while it is shifting downward for men.

Why focus on HDL?

Improvement in HDL is the strongest predictor of reduced risk for cardiac events. So says an analysis of 17 major lipid intervention trials between 1987 and 2003 (n = 44,170).²

Another study³ demonstrated that HDL cholesterol is the stronger predictor of CVD risk in women. In addition, several large observational studies have shown that increasing HDL cholesterol by 1 mg/dL in men reduces CVD risk by 2%, whereas increasing HDL in women by 1 mg/dL decreases CVD risk by 3%.⁴

Higher HDL levels may explain later onset of CVD in women. The advantage that women have over men in CVD risk prior to menopause seems to be at least partly due to their higher levels of HDL cholesterol: The average HDL level in women is 56 mg/dL, versus 46 mg/dL in men. This advantage begins to disappear after menopause, presumably because of changes in hormone levels and decreasing HDL-2 cholesterol, the most cardioprotective HDL fraction.

Other reasons to focus on HDL. In addition to the increased CVD risk associated with menopause, women of all ages in the United States have an increasing tendency—at almost epidemic rates—toward obesity and metabolic syndrome, which are known CVD risk factors.⁵ The dyslipidemia seen with those conditions is characterized by low HDL cholesterol and high triglycerides. Thus, maintaining healthy HDL levels is clearly an important goal for overall cardiovascular health, especially in women.

In addition, HDL is the key lipoprotein associated with reverse cholesterol transport, the process of carrying excess cholesterol from peripheral tissues to the liver for catabolism.

JUDY’S CASE

METABOLIC SYNDROME CONFIRMED

At her return visit, Judy’s blood pressure remains 140/90 mm Hg, with outside readings ranging from 135 to 145 mm Hg systolic and 85 to 95 mm Hg diastolic. Her laboratory tests reveal fasting blood glucose of 115 mg/dL, total cholesterol of 220 mg/dL, LDL cholesterol of 120 mg/dL, HDL cholesterol of 35 mg/dL, and triglycerides of 300 mg/dL.

What are her key heart-health issues?

Individualized management—recommended by NCEP/ATP III guidelines— should focus on reversing the metabolic defects of insulin resistance: hypertension, obesity, glucose intolerance, and dyslipidemia.

At present, Judy’s 10-year risk of a cardiac event is 4% by Framingham risk scoring, but it is likely to increase if the metabolic syndrome is not addressed.

How to preserve healthy HDL levels

Diet and regular aerobic exercise are recommended by the NCEP/ATP III guidelines, especially for obese patients with metabolic syndrome. However, dietary changes do not raise HDL cholesterol. In fact, dieting to lose weight will almost certainly lower HDL levels. That’s because people who eat a diet very low in fat tend to replace the fat calories with carbohydrates, and a low-fat, high-carbohydrate diet will reduce all cholesterol fractions—but HDL cholesterol will decrease disproportionately.⁶

Recommend complex carbohydrates and moderate fat intake

To avoid excessive reduction in HDL cholesterol, any weight-loss diet should involve moderate fat intake (35% of total calories) and emphasize monounsaturated fats such as olive or canola oil, along with complex carbohydrates found in fruits, vegetables, and whole grains.⁷ After weight loss is stabilized, HDL cholesterol tends to increase somewhat, but may not return all the way to baseline.

Regular exercise raises HDL

One way to avoid an overall reduction in HDL levels with weight loss is to prescribe exercise in conjunction with it. Regular exercise is an excellent way to raise HDL cholesterol levels. Studies suggest that, for women, the volume of exercise is more important than intensity. Thus, women should strive to walk 7 to 14 miles per week or otherwise expend approximately 1,200 to 1,600 Kcal.^8,9

Regular exercise is recommended as one of the NCEP/ATP III therapeutic lifestyle changes that directly benefit cardiovascular health and blood pressure and help the individual maintain optimal body weight. Although exercise raises HDL levels, it does so more easily in men than in women. HDL cholesterol increases in men with both intensity and volume of exercise.¹⁰ Women appear to derive slightly less of a benefit, perhaps because their HDL levels are already generally higher.

In women, studies have reported an increase in HDL cholesterol as high as 15% for both premenopausal and post-menopausal women who follow moderate exercise regimens—and the lower the baseline HDL level, the greater the increase.⁸

Exercise level was inversely associated with cardiovascular risk in the Women’s Health Initiative,⁹ which followed a cohort of 73,743 women prospectively for an average of 3.2 years. Women at the highest quintile of exercise level reduced their CVD risk by 53% over the lowest quintile, and moderate activity such as walking led to risk reductions similar to those involving more vigorous activities.

Recommend alcohol—or not?

Moderate alcohol consumption—1 to 3 drinks per day, or 15 to 45 g ethanol— improves lipoprotein levels and reduces CVD risk. The flavonoids in red wines also reduce platelet aggregation and clotting tendencies. However, advising a patient to consume alcohol to reduce her CVD risk is controversial; many physicians are reluctant to do so due to obvious concerns over toxicity and dependency.

Response to alcohol may vary by menopausal status. In 1 study,¹¹ pre-menopausal women decreased their LDL cholesterol by 12% (P=.01) after 3 glasses of wine daily for 3 weeks, but there was no significant increase in HDL levels.

In the same study, postmenopausal women increased HDL levels by 12% (P=.03), but their LDL cholesterol decreased only minimally.¹¹

Another study¹² in postmenopausal women who consumed 0, 1, or 2 drinks daily (0, 15, or 30 g ethanol) for 8 weeks showed a significant decrease of 4% in LDL cholesterol at 1 drink (15 g), but no significant further decrease at 2 drinks (30 g). In the same study, HDL increased non-significantly at 1 drink (15 g), but increased significantly (5%) at 2 drinks (30 g). There may be a threshold of 30 g ethanol daily for postmenopausal women to benefit significantly from alcohol consumption.

JUDY’S CASE

LIFESTYLE RECOMMENDATIONS

The foundation of Judy’s management should be the triad of weight loss, exercise, and a diet that limits refined carbohydrates and emphasizes fiber, fruits and vegetables, whole grains, and healthy fats (ie, olive, canola, and fish oils).

In prescribing exercise, emphasize quantity over intensity, such as 14 miles of walking weekly or 60 to 90 minutes daily of aerobic activity.

Since she has no history of cardiac symptoms, and low-intensity, high-quantity exercise is advised, she does not need a screening cardiac stress test before beginning her regimen.

Nutritional remedies

Pantethine

Pantethine is an over-the-counter (OTC) nutritional supplement that combines the B vitamin pantothenic acid with the amino acid cysteamine. Although pantothenic acid alone has no lipid-lowering effects, pantethine does: It lowers LDL cholesterol, very-low-density lipoprotein (VLDL) cholesterol, and triglycerides, and raises HDL levels. The exact mechanism of action is unknown, but it is thought to involve primarily the effects of cysteamine on lipid metabolism in the liver.

Recommended dose. At 600 to 900 mg daily, the typical response is an increase of up to 18% in HDL cholesterol and reductions in LDL cholesterol, VLDL cholesterol, and triglycerides of 13%, 20%, and 26%, respectively.¹³

In a recent US study, pantethine significantly raised HDL-2 cholesterol, the more cardioprotective fraction of HDL, and increased the particle size of LDL cholesterol, rendering it less atherogenic.¹⁴

Pantethine also reduces visceral fat. The same study¹⁴ reported a significant reduction in visceral fat, a component of metabolic syndrome, as measured by computerized dual-energy x-ray absorptiometry in individuals taking 900 mg daily for 6 weeks. This reduction appears to be primarily an effect of pantothenic acid and had been demonstrated in animal studies.

No side effects. Pantethine is exceptionally well tolerated, with virtually no side effects. An occasional person will experience gastrointestinal upset and diarrhea, which resolve when the drug is discontinued.

Recommend formulations that contain Pantesin (Daiichi Fine Chemicals, New York City), a pharmaceutical grade of pantethine, because extensive research confirms the benefits I have described. Otherwise, make sure the manufacturer is a reputable company, with scientific studies to support its claims of safety, efficacy, and bioavailability.

Nicotinic acid

Nicotinic acid (NA), another B vitamin available OTC as a nutritional supplement, is the most effective agent for raising HDL levels.

Recommended dose. A divided dose of 3,000 mg daily of the immediate-release form of NA can raise HDL levels as much as 30%. Unfortunately, that form of NA has a high incidence of adverse effects, such as flushing, itching, and GI upset.¹⁵

Sustained-release NA is generally well tolerated, but somewhat less effective at raising HDL. A lower dose of sustained-release NA (1,000 to 1,500 mg daily) is recommended to avoid liver toxicity and typically leads to HDL increases as high as 20%.¹⁵

NA offers additional benefits to the lipid profile, typically lowering LDL cholesterol by 20%, triglycerides by 15%, and lipoprotein(a) by 15%.¹⁵

Monitor all forms of NA with liver enzymes, blood glucose, and uric acid because treatment can elevate these markers.

Give NA preparations extra scrutiny. The general caveats about quality and bioavailability apply especially to NA. Nonprescription products on the market that contain nicotinamide and inositol hexanicotinate are advertised as “no-flush” niacin because they do not cause cutaneous side effects, but they also have no lipid benefits.

Cost. NA is relatively inexpensive, and good-quality sustained-release products such as Endur-acin (Endurance Products, Tigard, Ore) can be purchased OTC for 12 cents per 500-mg tablet or a daily cost of 24 to 36 cents.¹⁶

Sustained-release NA is also available by prescription (Niaspan, Kos Pharmaceuticals, Cranbury, NJ), but it is considerably more expensive ($1.98 per 500-mg tablet, or $3.96 to $5.94 daily) and has not been shown to be more effective or better tolerated than the better OTC products.¹⁶

JUDY’S CASE

RAISING HDL WITHOUT DRUGS

Judy’s lipid abnormalities would benefit from a supplement of pantethine (300 mg thrice daily) or NA (1,000 mg thrice daily of plain/quick release or 500 mg twice daily of sustained release to reduce flushing side effects).

Her greatest risk with her current lipid levels is low HDL, and the best agent to raise these levels is NA.

Pantethine also raises HDL and selectively improves the HDL-2 subfraction, which is most cardioprotective. Both supplements also improve the other lipid abnormalities.

In addition, referral to a dietician for detailed instruction in food choices and preparation may be useful.

Pharmacologic therapies

Hormone replacement therapy (HRT) is no longer recommended to prevent CVD and should be given only for menopausal symptoms during the perimenopausal years—despite the fact that estrogen has been shown to raise HDL cholesterol by 8% in postmenopausal women.¹⁷

Estrogens increase HDL by increasing production of apoA-1, the main lipoprotein in HDL, and by decreasing HDL catabolism by inhibiting hepatic lipase. The 17-hydroxyprogesterone component of HRT given to women with an intact uterus to prevent endometrial cancer has no significant lipid effects.

Paradoxically, the increased CVD risk found in the HRT arm of the Women’s Health Initiative¹⁷ was in the face of improved HDL (8%) and LDL (–14%) cholesterol and appeared to be the result of increased thrombotic events.

Further analysis of Women’s Health Initiative data showed that women who were still within 10 years of menopause actually did experience a reduction in CVD risk. That observation, along with some primate research on HRT, suggests that the risk or benefit of HRT with respect to CVD may be a matter of timing. See “Emerging hypothesis may explain estrogen paradox”

Statins and other HDL-modifying drugs

The statins are a first choice for LDL reduction, but lead to only modest increases (4%–10%) in HDL levels.¹⁸ Fibric acid derivatives are somewhat more effective; they lead to increases in HDL of 6% to 18%. Both types of drugs are considerably more expensive than OTC NA and not as effective at raising HDL.

Combining statins with other agents that raise HDL has been tried: The NA–statin combination can be effective in managing dyslipidemias of both LDL and HDL. Fibric acid derivatives should not be used with statins because of the increased risk of serious myopathies.¹⁸

JUDY’S CASE

THERAPEUTIC TARGETS

Judy’s goals should include:

• reducing blood pressure to less than 120/80 mm Hg,
• decreasing weight to about 140 lb,
• achieving a waist measurement of less than 35 inches,
• reducing fasting blood glucose to less than 100 mg/dL,
• decreasing triglycerides to less than 150 mg/dL, total cholesterol to less than 200 mg/dL, and LDL levels to less than 100 mg/dL, and
• raising HDL to more than 45 mg/dL.

All these parameters should be checked every 3 months until the goals are achieved.

If Judy fails to progress or develops symptoms of heart disease, she should be referred to a cardiologist for further evaluation and more aggressive treatment.

The author reports no conflicts relevant to this article.

JUDY’S CASE

“WHAT’S MY RISK?”

At her periodic gynecologic exam, Judy, a 58-year-old white woman, expresses concern about her heart health in light of her 62-year-old sister’s recent heart attack. Further questioning reveals that her father died of a heart attack at age 56, and her brother, 52, has high blood pressure and adult-onset diabetes.

Judy has not experienced any symptoms of cardiovascular disease, such as chest pain or tightness with exertion, and she doesn’t smoke. The last time her cholesterol was checked was about 15 years earlier, at which time it was “OK.” She admits she is not very physically active and has gained about 30 lb over the past 10 years. Her vital signs and physical exam are entirely normal except for borderline high blood pressure at 140/90 mm Hg, weight of 170 lb (height: 68 inches), and a waist circumference of 37 inches.

What is her cardiovascular risk?

Judy has physical findings suggestive of metabolic syndrome in addition to the significant family history of cardiovascular disease (CVD). Although her current risk of a cardiac event appears to be low, she is likely to deteriorate if the hypertension and excess body weight are not addressed.

To predict her level of risk more precisely, the physician asks Judy to return in 2 weeks for a blood pressure recheck, and instructs her to perform additional readings on her own. The clinician also refers Judy for a fasting lipid panel and blood glucose level.

In women, CVD is especially lethal

Contrary to earlier assumptions, CVD now appears to be more lethal in women than in men and warrants aggressive efforts to prevent it and manage risk factors (FIGURE). This article focuses on improving high-density lipoprotein (HDL) cholesterol, a key factor in women at risk.

This approach differs slightly from the National Cholesterol Education Program Adult Treatment Panel III (NCEP/ATP III) guidelines, which target low-density lipoprotein (LDL) cholesterol as the primary lipid risk factor for intervention.¹

FIGURE Women surpass men in CVD deaths

Over the past 25 years, the trend in deaths attributable to cardiovascular disease has been upward for women, while it is shifting downward for men.

Why focus on HDL?

Improvement in HDL is the strongest predictor of reduced risk for cardiac events. So says an analysis of 17 major lipid intervention trials between 1987 and 2003 (n = 44,170).²

Another study³ demonstrated that HDL cholesterol is the stronger predictor of CVD risk in women. In addition, several large observational studies have shown that increasing HDL cholesterol by 1 mg/dL in men reduces CVD risk by 2%, whereas increasing HDL in women by 1 mg/dL decreases CVD risk by 3%.⁴

Higher HDL levels may explain later onset of CVD in women. The advantage that women have over men in CVD risk prior to menopause seems to be at least partly due to their higher levels of HDL cholesterol: The average HDL level in women is 56 mg/dL, versus 46 mg/dL in men. This advantage begins to disappear after menopause, presumably because of changes in hormone levels and decreasing HDL-2 cholesterol, the most cardioprotective HDL fraction.

Other reasons to focus on HDL. In addition to the increased CVD risk associated with menopause, women of all ages in the United States have an increasing tendency—at almost epidemic rates—toward obesity and metabolic syndrome, which are known CVD risk factors.⁵ The dyslipidemia seen with those conditions is characterized by low HDL cholesterol and high triglycerides. Thus, maintaining healthy HDL levels is clearly an important goal for overall cardiovascular health, especially in women.

In addition, HDL is the key lipoprotein associated with reverse cholesterol transport, the process of carrying excess cholesterol from peripheral tissues to the liver for catabolism.

JUDY’S CASE

METABOLIC SYNDROME CONFIRMED

At her return visit, Judy’s blood pressure remains 140/90 mm Hg, with outside readings ranging from 135 to 145 mm Hg systolic and 85 to 95 mm Hg diastolic. Her laboratory tests reveal fasting blood glucose of 115 mg/dL, total cholesterol of 220 mg/dL, LDL cholesterol of 120 mg/dL, HDL cholesterol of 35 mg/dL, and triglycerides of 300 mg/dL.

What are her key heart-health issues?

Individualized management—recommended by NCEP/ATP III guidelines— should focus on reversing the metabolic defects of insulin resistance: hypertension, obesity, glucose intolerance, and dyslipidemia.

At present, Judy’s 10-year risk of a cardiac event is 4% by Framingham risk scoring, but it is likely to increase if the metabolic syndrome is not addressed.

How to preserve healthy HDL levels

Diet and regular aerobic exercise are recommended by the NCEP/ATP III guidelines, especially for obese patients with metabolic syndrome. However, dietary changes do not raise HDL cholesterol. In fact, dieting to lose weight will almost certainly lower HDL levels. That’s because people who eat a diet very low in fat tend to replace the fat calories with carbohydrates, and a low-fat, high-carbohydrate diet will reduce all cholesterol fractions—but HDL cholesterol will decrease disproportionately.⁶

Recommend complex carbohydrates and moderate fat intake

To avoid excessive reduction in HDL cholesterol, any weight-loss diet should involve moderate fat intake (35% of total calories) and emphasize monounsaturated fats such as olive or canola oil, along with complex carbohydrates found in fruits, vegetables, and whole grains.⁷ After weight loss is stabilized, HDL cholesterol tends to increase somewhat, but may not return all the way to baseline.

Regular exercise raises HDL

One way to avoid an overall reduction in HDL levels with weight loss is to prescribe exercise in conjunction with it. Regular exercise is an excellent way to raise HDL cholesterol levels. Studies suggest that, for women, the volume of exercise is more important than intensity. Thus, women should strive to walk 7 to 14 miles per week or otherwise expend approximately 1,200 to 1,600 Kcal.^8,9

Regular exercise is recommended as one of the NCEP/ATP III therapeutic lifestyle changes that directly benefit cardiovascular health and blood pressure and help the individual maintain optimal body weight. Although exercise raises HDL levels, it does so more easily in men than in women. HDL cholesterol increases in men with both intensity and volume of exercise.¹⁰ Women appear to derive slightly less of a benefit, perhaps because their HDL levels are already generally higher.

In women, studies have reported an increase in HDL cholesterol as high as 15% for both premenopausal and post-menopausal women who follow moderate exercise regimens—and the lower the baseline HDL level, the greater the increase.⁸

Exercise level was inversely associated with cardiovascular risk in the Women’s Health Initiative,⁹ which followed a cohort of 73,743 women prospectively for an average of 3.2 years. Women at the highest quintile of exercise level reduced their CVD risk by 53% over the lowest quintile, and moderate activity such as walking led to risk reductions similar to those involving more vigorous activities.

Recommend alcohol—or not?

Moderate alcohol consumption—1 to 3 drinks per day, or 15 to 45 g ethanol— improves lipoprotein levels and reduces CVD risk. The flavonoids in red wines also reduce platelet aggregation and clotting tendencies. However, advising a patient to consume alcohol to reduce her CVD risk is controversial; many physicians are reluctant to do so due to obvious concerns over toxicity and dependency.

Response to alcohol may vary by menopausal status. In 1 study,¹¹ pre-menopausal women decreased their LDL cholesterol by 12% (P=.01) after 3 glasses of wine daily for 3 weeks, but there was no significant increase in HDL levels.

In the same study, postmenopausal women increased HDL levels by 12% (P=.03), but their LDL cholesterol decreased only minimally.¹¹

Another study¹² in postmenopausal women who consumed 0, 1, or 2 drinks daily (0, 15, or 30 g ethanol) for 8 weeks showed a significant decrease of 4% in LDL cholesterol at 1 drink (15 g), but no significant further decrease at 2 drinks (30 g). In the same study, HDL increased non-significantly at 1 drink (15 g), but increased significantly (5%) at 2 drinks (30 g). There may be a threshold of 30 g ethanol daily for postmenopausal women to benefit significantly from alcohol consumption.

JUDY’S CASE

LIFESTYLE RECOMMENDATIONS

The foundation of Judy’s management should be the triad of weight loss, exercise, and a diet that limits refined carbohydrates and emphasizes fiber, fruits and vegetables, whole grains, and healthy fats (ie, olive, canola, and fish oils).

In prescribing exercise, emphasize quantity over intensity, such as 14 miles of walking weekly or 60 to 90 minutes daily of aerobic activity.

Since she has no history of cardiac symptoms, and low-intensity, high-quantity exercise is advised, she does not need a screening cardiac stress test before beginning her regimen.

Nutritional remedies

Pantethine

Pantethine is an over-the-counter (OTC) nutritional supplement that combines the B vitamin pantothenic acid with the amino acid cysteamine. Although pantothenic acid alone has no lipid-lowering effects, pantethine does: It lowers LDL cholesterol, very-low-density lipoprotein (VLDL) cholesterol, and triglycerides, and raises HDL levels. The exact mechanism of action is unknown, but it is thought to involve primarily the effects of cysteamine on lipid metabolism in the liver.

Recommended dose. At 600 to 900 mg daily, the typical response is an increase of up to 18% in HDL cholesterol and reductions in LDL cholesterol, VLDL cholesterol, and triglycerides of 13%, 20%, and 26%, respectively.¹³

In a recent US study, pantethine significantly raised HDL-2 cholesterol, the more cardioprotective fraction of HDL, and increased the particle size of LDL cholesterol, rendering it less atherogenic.¹⁴

Pantethine also reduces visceral fat. The same study¹⁴ reported a significant reduction in visceral fat, a component of metabolic syndrome, as measured by computerized dual-energy x-ray absorptiometry in individuals taking 900 mg daily for 6 weeks. This reduction appears to be primarily an effect of pantothenic acid and had been demonstrated in animal studies.

No side effects. Pantethine is exceptionally well tolerated, with virtually no side effects. An occasional person will experience gastrointestinal upset and diarrhea, which resolve when the drug is discontinued.

Recommend formulations that contain Pantesin (Daiichi Fine Chemicals, New York City), a pharmaceutical grade of pantethine, because extensive research confirms the benefits I have described. Otherwise, make sure the manufacturer is a reputable company, with scientific studies to support its claims of safety, efficacy, and bioavailability.

Nicotinic acid

Nicotinic acid (NA), another B vitamin available OTC as a nutritional supplement, is the most effective agent for raising HDL levels.

Recommended dose. A divided dose of 3,000 mg daily of the immediate-release form of NA can raise HDL levels as much as 30%. Unfortunately, that form of NA has a high incidence of adverse effects, such as flushing, itching, and GI upset.¹⁵

Sustained-release NA is generally well tolerated, but somewhat less effective at raising HDL. A lower dose of sustained-release NA (1,000 to 1,500 mg daily) is recommended to avoid liver toxicity and typically leads to HDL increases as high as 20%.¹⁵

NA offers additional benefits to the lipid profile, typically lowering LDL cholesterol by 20%, triglycerides by 15%, and lipoprotein(a) by 15%.¹⁵

Monitor all forms of NA with liver enzymes, blood glucose, and uric acid because treatment can elevate these markers.

Give NA preparations extra scrutiny. The general caveats about quality and bioavailability apply especially to NA. Nonprescription products on the market that contain nicotinamide and inositol hexanicotinate are advertised as “no-flush” niacin because they do not cause cutaneous side effects, but they also have no lipid benefits.

Cost. NA is relatively inexpensive, and good-quality sustained-release products such as Endur-acin (Endurance Products, Tigard, Ore) can be purchased OTC for 12 cents per 500-mg tablet or a daily cost of 24 to 36 cents.¹⁶

Sustained-release NA is also available by prescription (Niaspan, Kos Pharmaceuticals, Cranbury, NJ), but it is considerably more expensive ($1.98 per 500-mg tablet, or $3.96 to $5.94 daily) and has not been shown to be more effective or better tolerated than the better OTC products.¹⁶

JUDY’S CASE

RAISING HDL WITHOUT DRUGS

Judy’s lipid abnormalities would benefit from a supplement of pantethine (300 mg thrice daily) or NA (1,000 mg thrice daily of plain/quick release or 500 mg twice daily of sustained release to reduce flushing side effects).

Her greatest risk with her current lipid levels is low HDL, and the best agent to raise these levels is NA.

Pantethine also raises HDL and selectively improves the HDL-2 subfraction, which is most cardioprotective. Both supplements also improve the other lipid abnormalities.

In addition, referral to a dietician for detailed instruction in food choices and preparation may be useful.

Pharmacologic therapies

Hormone replacement therapy (HRT) is no longer recommended to prevent CVD and should be given only for menopausal symptoms during the perimenopausal years—despite the fact that estrogen has been shown to raise HDL cholesterol by 8% in postmenopausal women.¹⁷

Estrogens increase HDL by increasing production of apoA-1, the main lipoprotein in HDL, and by decreasing HDL catabolism by inhibiting hepatic lipase. The 17-hydroxyprogesterone component of HRT given to women with an intact uterus to prevent endometrial cancer has no significant lipid effects.

Paradoxically, the increased CVD risk found in the HRT arm of the Women’s Health Initiative¹⁷ was in the face of improved HDL (8%) and LDL (–14%) cholesterol and appeared to be the result of increased thrombotic events.

Further analysis of Women’s Health Initiative data showed that women who were still within 10 years of menopause actually did experience a reduction in CVD risk. That observation, along with some primate research on HRT, suggests that the risk or benefit of HRT with respect to CVD may be a matter of timing. See “Emerging hypothesis may explain estrogen paradox”

Statins and other HDL-modifying drugs

The statins are a first choice for LDL reduction, but lead to only modest increases (4%–10%) in HDL levels.¹⁸ Fibric acid derivatives are somewhat more effective; they lead to increases in HDL of 6% to 18%. Both types of drugs are considerably more expensive than OTC NA and not as effective at raising HDL.

Combining statins with other agents that raise HDL has been tried: The NA–statin combination can be effective in managing dyslipidemias of both LDL and HDL. Fibric acid derivatives should not be used with statins because of the increased risk of serious myopathies.¹⁸

JUDY’S CASE

THERAPEUTIC TARGETS

Judy’s goals should include:

• reducing blood pressure to less than 120/80 mm Hg,
• decreasing weight to about 140 lb,
• achieving a waist measurement of less than 35 inches,
• reducing fasting blood glucose to less than 100 mg/dL,
• decreasing triglycerides to less than 150 mg/dL, total cholesterol to less than 200 mg/dL, and LDL levels to less than 100 mg/dL, and
• raising HDL to more than 45 mg/dL.

All these parameters should be checked every 3 months until the goals are achieved.

If Judy fails to progress or develops symptoms of heart disease, she should be referred to a cardiologist for further evaluation and more aggressive treatment.

The author reports no conflicts relevant to this article.

JUDY’S CASE

“WHAT’S MY RISK?”

At her periodic gynecologic exam, Judy, a 58-year-old white woman, expresses concern about her heart health in light of her 62-year-old sister’s recent heart attack. Further questioning reveals that her father died of a heart attack at age 56, and her brother, 52, has high blood pressure and adult-onset diabetes.

Judy has not experienced any symptoms of cardiovascular disease, such as chest pain or tightness with exertion, and she doesn’t smoke. The last time her cholesterol was checked was about 15 years earlier, at which time it was “OK.” She admits she is not very physically active and has gained about 30 lb over the past 10 years. Her vital signs and physical exam are entirely normal except for borderline high blood pressure at 140/90 mm Hg, weight of 170 lb (height: 68 inches), and a waist circumference of 37 inches.

What is her cardiovascular risk?

Judy has physical findings suggestive of metabolic syndrome in addition to the significant family history of cardiovascular disease (CVD). Although her current risk of a cardiac event appears to be low, she is likely to deteriorate if the hypertension and excess body weight are not addressed.

To predict her level of risk more precisely, the physician asks Judy to return in 2 weeks for a blood pressure recheck, and instructs her to perform additional readings on her own. The clinician also refers Judy for a fasting lipid panel and blood glucose level.

In women, CVD is especially lethal

Contrary to earlier assumptions, CVD now appears to be more lethal in women than in men and warrants aggressive efforts to prevent it and manage risk factors (FIGURE). This article focuses on improving high-density lipoprotein (HDL) cholesterol, a key factor in women at risk.

This approach differs slightly from the National Cholesterol Education Program Adult Treatment Panel III (NCEP/ATP III) guidelines, which target low-density lipoprotein (LDL) cholesterol as the primary lipid risk factor for intervention.¹

FIGURE Women surpass men in CVD deaths

Over the past 25 years, the trend in deaths attributable to cardiovascular disease has been upward for women, while it is shifting downward for men.

Why focus on HDL?

Improvement in HDL is the strongest predictor of reduced risk for cardiac events. So says an analysis of 17 major lipid intervention trials between 1987 and 2003 (n = 44,170).²

Another study³ demonstrated that HDL cholesterol is the stronger predictor of CVD risk in women. In addition, several large observational studies have shown that increasing HDL cholesterol by 1 mg/dL in men reduces CVD risk by 2%, whereas increasing HDL in women by 1 mg/dL decreases CVD risk by 3%.⁴

Higher HDL levels may explain later onset of CVD in women. The advantage that women have over men in CVD risk prior to menopause seems to be at least partly due to their higher levels of HDL cholesterol: The average HDL level in women is 56 mg/dL, versus 46 mg/dL in men. This advantage begins to disappear after menopause, presumably because of changes in hormone levels and decreasing HDL-2 cholesterol, the most cardioprotective HDL fraction.

Other reasons to focus on HDL. In addition to the increased CVD risk associated with menopause, women of all ages in the United States have an increasing tendency—at almost epidemic rates—toward obesity and metabolic syndrome, which are known CVD risk factors.⁵ The dyslipidemia seen with those conditions is characterized by low HDL cholesterol and high triglycerides. Thus, maintaining healthy HDL levels is clearly an important goal for overall cardiovascular health, especially in women.

In addition, HDL is the key lipoprotein associated with reverse cholesterol transport, the process of carrying excess cholesterol from peripheral tissues to the liver for catabolism.

JUDY’S CASE

METABOLIC SYNDROME CONFIRMED

At her return visit, Judy’s blood pressure remains 140/90 mm Hg, with outside readings ranging from 135 to 145 mm Hg systolic and 85 to 95 mm Hg diastolic. Her laboratory tests reveal fasting blood glucose of 115 mg/dL, total cholesterol of 220 mg/dL, LDL cholesterol of 120 mg/dL, HDL cholesterol of 35 mg/dL, and triglycerides of 300 mg/dL.

What are her key heart-health issues?

Individualized management—recommended by NCEP/ATP III guidelines— should focus on reversing the metabolic defects of insulin resistance: hypertension, obesity, glucose intolerance, and dyslipidemia.

At present, Judy’s 10-year risk of a cardiac event is 4% by Framingham risk scoring, but it is likely to increase if the metabolic syndrome is not addressed.

How to preserve healthy HDL levels

Diet and regular aerobic exercise are recommended by the NCEP/ATP III guidelines, especially for obese patients with metabolic syndrome. However, dietary changes do not raise HDL cholesterol. In fact, dieting to lose weight will almost certainly lower HDL levels. That’s because people who eat a diet very low in fat tend to replace the fat calories with carbohydrates, and a low-fat, high-carbohydrate diet will reduce all cholesterol fractions—but HDL cholesterol will decrease disproportionately.⁶

Recommend complex carbohydrates and moderate fat intake

To avoid excessive reduction in HDL cholesterol, any weight-loss diet should involve moderate fat intake (35% of total calories) and emphasize monounsaturated fats such as olive or canola oil, along with complex carbohydrates found in fruits, vegetables, and whole grains.⁷ After weight loss is stabilized, HDL cholesterol tends to increase somewhat, but may not return all the way to baseline.

Regular exercise raises HDL

One way to avoid an overall reduction in HDL levels with weight loss is to prescribe exercise in conjunction with it. Regular exercise is an excellent way to raise HDL cholesterol levels. Studies suggest that, for women, the volume of exercise is more important than intensity. Thus, women should strive to walk 7 to 14 miles per week or otherwise expend approximately 1,200 to 1,600 Kcal.^8,9

Regular exercise is recommended as one of the NCEP/ATP III therapeutic lifestyle changes that directly benefit cardiovascular health and blood pressure and help the individual maintain optimal body weight. Although exercise raises HDL levels, it does so more easily in men than in women. HDL cholesterol increases in men with both intensity and volume of exercise.¹⁰ Women appear to derive slightly less of a benefit, perhaps because their HDL levels are already generally higher.

In women, studies have reported an increase in HDL cholesterol as high as 15% for both premenopausal and post-menopausal women who follow moderate exercise regimens—and the lower the baseline HDL level, the greater the increase.⁸

Exercise level was inversely associated with cardiovascular risk in the Women’s Health Initiative,⁹ which followed a cohort of 73,743 women prospectively for an average of 3.2 years. Women at the highest quintile of exercise level reduced their CVD risk by 53% over the lowest quintile, and moderate activity such as walking led to risk reductions similar to those involving more vigorous activities.

Recommend alcohol—or not?

Moderate alcohol consumption—1 to 3 drinks per day, or 15 to 45 g ethanol— improves lipoprotein levels and reduces CVD risk. The flavonoids in red wines also reduce platelet aggregation and clotting tendencies. However, advising a patient to consume alcohol to reduce her CVD risk is controversial; many physicians are reluctant to do so due to obvious concerns over toxicity and dependency.

Response to alcohol may vary by menopausal status. In 1 study,¹¹ pre-menopausal women decreased their LDL cholesterol by 12% (P=.01) after 3 glasses of wine daily for 3 weeks, but there was no significant increase in HDL levels.

In the same study, postmenopausal women increased HDL levels by 12% (P=.03), but their LDL cholesterol decreased only minimally.¹¹

Another study¹² in postmenopausal women who consumed 0, 1, or 2 drinks daily (0, 15, or 30 g ethanol) for 8 weeks showed a significant decrease of 4% in LDL cholesterol at 1 drink (15 g), but no significant further decrease at 2 drinks (30 g). In the same study, HDL increased non-significantly at 1 drink (15 g), but increased significantly (5%) at 2 drinks (30 g). There may be a threshold of 30 g ethanol daily for postmenopausal women to benefit significantly from alcohol consumption.

JUDY’S CASE

LIFESTYLE RECOMMENDATIONS

The foundation of Judy’s management should be the triad of weight loss, exercise, and a diet that limits refined carbohydrates and emphasizes fiber, fruits and vegetables, whole grains, and healthy fats (ie, olive, canola, and fish oils).

In prescribing exercise, emphasize quantity over intensity, such as 14 miles of walking weekly or 60 to 90 minutes daily of aerobic activity.

Since she has no history of cardiac symptoms, and low-intensity, high-quantity exercise is advised, she does not need a screening cardiac stress test before beginning her regimen.

Nutritional remedies

Pantethine

Pantethine is an over-the-counter (OTC) nutritional supplement that combines the B vitamin pantothenic acid with the amino acid cysteamine. Although pantothenic acid alone has no lipid-lowering effects, pantethine does: It lowers LDL cholesterol, very-low-density lipoprotein (VLDL) cholesterol, and triglycerides, and raises HDL levels. The exact mechanism of action is unknown, but it is thought to involve primarily the effects of cysteamine on lipid metabolism in the liver.

Recommended dose. At 600 to 900 mg daily, the typical response is an increase of up to 18% in HDL cholesterol and reductions in LDL cholesterol, VLDL cholesterol, and triglycerides of 13%, 20%, and 26%, respectively.¹³

In a recent US study, pantethine significantly raised HDL-2 cholesterol, the more cardioprotective fraction of HDL, and increased the particle size of LDL cholesterol, rendering it less atherogenic.¹⁴

Pantethine also reduces visceral fat. The same study¹⁴ reported a significant reduction in visceral fat, a component of metabolic syndrome, as measured by computerized dual-energy x-ray absorptiometry in individuals taking 900 mg daily for 6 weeks. This reduction appears to be primarily an effect of pantothenic acid and had been demonstrated in animal studies.

No side effects. Pantethine is exceptionally well tolerated, with virtually no side effects. An occasional person will experience gastrointestinal upset and diarrhea, which resolve when the drug is discontinued.

Recommend formulations that contain Pantesin (Daiichi Fine Chemicals, New York City), a pharmaceutical grade of pantethine, because extensive research confirms the benefits I have described. Otherwise, make sure the manufacturer is a reputable company, with scientific studies to support its claims of safety, efficacy, and bioavailability.

Nicotinic acid

Nicotinic acid (NA), another B vitamin available OTC as a nutritional supplement, is the most effective agent for raising HDL levels.

Recommended dose. A divided dose of 3,000 mg daily of the immediate-release form of NA can raise HDL levels as much as 30%. Unfortunately, that form of NA has a high incidence of adverse effects, such as flushing, itching, and GI upset.¹⁵

Sustained-release NA is generally well tolerated, but somewhat less effective at raising HDL. A lower dose of sustained-release NA (1,000 to 1,500 mg daily) is recommended to avoid liver toxicity and typically leads to HDL increases as high as 20%.¹⁵

NA offers additional benefits to the lipid profile, typically lowering LDL cholesterol by 20%, triglycerides by 15%, and lipoprotein(a) by 15%.¹⁵

Monitor all forms of NA with liver enzymes, blood glucose, and uric acid because treatment can elevate these markers.

Give NA preparations extra scrutiny. The general caveats about quality and bioavailability apply especially to NA. Nonprescription products on the market that contain nicotinamide and inositol hexanicotinate are advertised as “no-flush” niacin because they do not cause cutaneous side effects, but they also have no lipid benefits.

Cost. NA is relatively inexpensive, and good-quality sustained-release products such as Endur-acin (Endurance Products, Tigard, Ore) can be purchased OTC for 12 cents per 500-mg tablet or a daily cost of 24 to 36 cents.¹⁶

Sustained-release NA is also available by prescription (Niaspan, Kos Pharmaceuticals, Cranbury, NJ), but it is considerably more expensive ($1.98 per 500-mg tablet, or $3.96 to $5.94 daily) and has not been shown to be more effective or better tolerated than the better OTC products.¹⁶

JUDY’S CASE

RAISING HDL WITHOUT DRUGS

Judy’s lipid abnormalities would benefit from a supplement of pantethine (300 mg thrice daily) or NA (1,000 mg thrice daily of plain/quick release or 500 mg twice daily of sustained release to reduce flushing side effects).

Her greatest risk with her current lipid levels is low HDL, and the best agent to raise these levels is NA.

Pantethine also raises HDL and selectively improves the HDL-2 subfraction, which is most cardioprotective. Both supplements also improve the other lipid abnormalities.

In addition, referral to a dietician for detailed instruction in food choices and preparation may be useful.

Pharmacologic therapies

Hormone replacement therapy (HRT) is no longer recommended to prevent CVD and should be given only for menopausal symptoms during the perimenopausal years—despite the fact that estrogen has been shown to raise HDL cholesterol by 8% in postmenopausal women.¹⁷

Estrogens increase HDL by increasing production of apoA-1, the main lipoprotein in HDL, and by decreasing HDL catabolism by inhibiting hepatic lipase. The 17-hydroxyprogesterone component of HRT given to women with an intact uterus to prevent endometrial cancer has no significant lipid effects.

Paradoxically, the increased CVD risk found in the HRT arm of the Women’s Health Initiative¹⁷ was in the face of improved HDL (8%) and LDL (–14%) cholesterol and appeared to be the result of increased thrombotic events.

Further analysis of Women’s Health Initiative data showed that women who were still within 10 years of menopause actually did experience a reduction in CVD risk. That observation, along with some primate research on HRT, suggests that the risk or benefit of HRT with respect to CVD may be a matter of timing. See “Emerging hypothesis may explain estrogen paradox”

Statins and other HDL-modifying drugs

The statins are a first choice for LDL reduction, but lead to only modest increases (4%–10%) in HDL levels.¹⁸ Fibric acid derivatives are somewhat more effective; they lead to increases in HDL of 6% to 18%. Both types of drugs are considerably more expensive than OTC NA and not as effective at raising HDL.

Combining statins with other agents that raise HDL has been tried: The NA–statin combination can be effective in managing dyslipidemias of both LDL and HDL. Fibric acid derivatives should not be used with statins because of the increased risk of serious myopathies.¹⁸

JUDY’S CASE

THERAPEUTIC TARGETS

Judy’s goals should include:

• reducing blood pressure to less than 120/80 mm Hg,
• decreasing weight to about 140 lb,
• achieving a waist measurement of less than 35 inches,
• reducing fasting blood glucose to less than 100 mg/dL,
• decreasing triglycerides to less than 150 mg/dL, total cholesterol to less than 200 mg/dL, and LDL levels to less than 100 mg/dL, and
• raising HDL to more than 45 mg/dL.

All these parameters should be checked every 3 months until the goals are achieved.

If Judy fails to progress or develops symptoms of heart disease, she should be referred to a cardiologist for further evaluation and more aggressive treatment.

The author reports no conflicts relevant to this article.

Time and study make a difference. So does careful review and reappraisal of existing data. In the past year, the pendulum has swung away from fear of hormone therapy to a better understanding of indications, risks and benefits—an understanding driven largely by the evidence-based position statements of the North American Menopause Society (NAMS).

A meta-analysis of randomized controlled trials of phytoestrogens attested to lack of efficacy or weak effect, which helps clear the picture on soy and red clover, but the researchers stressed that the lack of quality control does not rule out the possibility that some products might carry steroidal effects and potential risk.

And another year has brought even more evidence that diet, exercise, smoking cessation and the like really do improve health and quality of life.

Advisory on hormone therapy and “bio-identicals”

The NAMS Hormone Therapy Panel concluded definitively that bio-identical hormones should be considered in the same category as all the sex steroids, which, in the absence of specific safety and efficacy studies, carry the same risks and benefits as related products.

On the other hand, alternatives do exist for specific indications, such as bisphosphonates for bone conservation.

The new NAMSPosition Statement stresses individualized treatment based on the recommendations below.

The full report is available at www.menopause.org.

• Treatment of moderate to severe menopausal symptoms is the primary indications for systemic therapy. Every systemic product is FDA-approved for this indication.
• Every systemic and local product is approved for moderate vulvar and vaginal atrophy. For this indication alone, local ET is generally advised.
• Duration should be for the lowest effective dose and shortest time consistent with treatment goals.
• If the woman is well aware of potential risks and benefits, and if there is clinical supervision, extended use of the lowest effective ET/EPT dose for treatment goals is acceptable in women who believe the benefits outweigh the risks, for those at high risk of osteoporotic fracture who also have moderate to severe menopause symptoms, for further prevention of established bone loss when alternate therapies are not appropriate or cause side effects, or when outcomes of extended use of those therapies are not known.
• Although specific compounds, doses, and routes of administration may have different outcomes, clinical trial results for one agent should be generalized to all agents within the same family in the absence of data for each specific product. This proviso also applies to the so-called bioidentical products.

Question marks

The Hormone Therapy panel could not agree unanimously on these questions:

• Should women who are doing well on long-term HT discontinue?
• What is the best way to discontinue HT, abrupt cessation or tapering?
• Is the effect of continuous-combined EPT different from that of continuous estrogen with sequential progestogen?
• How definitive is the evidence on early increased CHD risk with HT?
• Conflicting data precluded a consensus on adverse breast cancer and cardiovascular outcomes associated with ET/EPT.

ACKNOWLEDGMENTS

The following commentaries on key papers are from the NAMS First To Knowemail program for members. I thank the members of NAMS who have taken time out to provide these objective reviews of the studies presented here, and Phil Lammers, NAMS Medical Editor.

OSTEOPOROSISCurb your enthusiasm—no need to rush bone drugs if risk is low

McClung MR, Wasnich RD, Hosking DJ, et al, on behalf of the Early Postmenopausal Intervention Cohort (EPIC) study group. Prevention of postmenopausal bone loss: six-year results from the early postmenopausal intervention cohort study. J Clin Endocrinol Metab 2004;89:4879-4885. LEVEL 1 EVIDENCE: Randomized, controlled trial

Women in their 50s are not melting away. Their bones are not dissolving out from under them, contrary to what many media reports would have ObGyns and patients believe. Still, many clinicians are enthusiastic about prescribing bone drugs like bisphosphonates to women in their 50s who are generally healthy. (And there is no doubt that we do have bone drugs found to be safe and effective in well-designed trials, including the EPIC study.)

Yet there has been a major shift away from starting osteoporosis prevention drugs soon after menopause. EPIC data add support for a “go slow” strategy for drug intervention in healthy women in their 50s.

The EPIC study involved a total of 1,609 women ages 45 to 59, who received alendronate or placebo in a double-blind, randomized design. BMD was measured annually. The 4-year results were reported previously, and the 6-year results were published just last fall. Not surprisingly, women using alendronate had some increase in BMD and some reduction in bone turnover markers. But the results in the women who took placebo are of singular interest.

After 6 years, women on placebo had lost very little bone. The amount lost was statistically significant, but clinically inconsequential. The average BMD in women on placebo decreased 3% in the spine and 2% in the hip. Thus, the average rate of bone loss was about 0.5% per year.

A bone mass decrease of this extent represents a decline of about -0.3 T score, which is negligible. In the EPIC study, the 6-year fracture benefit, based on any type of fracture, boils down to lowering the risk from 1 in 11 on placebo to 1 in 9 on alendronate. These healthy women in their 50s had a very low risk of fracture, and taking a drug for 6 years had very little benefit for fracture reduction.

Women in their 50s typically have about 10% to 15% less bone mass than women of 25 to 30, when bone mass is at its peak. That 10% to 15% lower BMD translates to a T score of –1 to –1.2 , which is currently being labeled as osteopenic. Many patients and physicians have come to feel that osteopenia must always be treated with our newer drugs.

We are discovering that starting healthy women in their 50s on osteoporosis prevention drugs carries an extremely high cost per fracture avoided. During the 10 years since the startup of the EPIC study, support for early drug intervention in healthy women still in their 50s has dwindled. Now, expert groups, including the National Osteoporosis Foundation and the US Preventive Services Task Force, advise waiting until age 65 before starting osteoporosis risk evaluation or considering drug intervention in women who are otherwise healthy.

In my practice, I give healthy women in their 50s permission not to take drugs if their risk of fracture within the next 5 to 10 years is low. The picture is quite different in postmenopausal women in their 50s who do have high fracture risk, such as those who have already had a fracture, or who have very low bone density or high exposure to glucocorticoids.

EPIC data support the concept that the rate of bone loss is quite slow after a year or 2 has elapsed after menopause.

We need to avoid medicalizing these patients simply because we have drugs that reduce bone loss or because women in their 50s have less bone mass than 25-year-olds.

BIBLIOGRAPHY

Hosking D, Chilvers CE, Christiansen C, et al. Prevention of bone loss with alendronate in postmenopausal women under 60 years of age. Early Postmenopausal Intervention Cohort Study Group. N Engl J Med. 1998;338:485-492.

Wasnich RD, Bagger YZ, Hosking DJ, et al. Changes in bone density and turnover after alendronate or estrogen withdrawal. Menopause. 2004;11:622-630.

Siris ES, Bilezikian JP, Rubin MR, et al. Pins and plasters aren’t enough: a call for the evaluation and treatment of patients with osteoporotic fractures. J Clin Endocrinol Metab. 2003;88:3482-3486.

Rosen CJ, Black DM, Greenspan SL. Vignettes in osteoporosis: a road map to successful therapeutics. J Bone Miner Res. 2004;19:3-10.

HORMONE THERAPYDoes age affect mortality rate in postmenopausal women using HT?

Salpeter SR, Walsh JME, Greyber E, Ormiston TM, Salpeter EE. Mortality associated with hormone replacement therapy in younger and older women. J Gen Intern Med. 2004;19:791–804. META-ANALYSIS

This study attempted to discover whether the age of the postmenopausal woman using hormone therapy affects mortality. Investigators performed a meta-analysis of clinical trials that reported mortality rates associated with use of postmenopausal hormone therapy, and analyzed the results based on mean ages.

They reported a significant trend between increasing risk of mortality and increasing mean age of the women using hormone therapy—raising the possibility of a health benefit for younger postmenopausal women.

The studies included in the metaanalysis varied in entry criteria, outcomes assessed, number of subjects, and HT type and dosage. Furthermore, because age groups were defined by mean age in each trial rather than actual age of pooled participants, some overlap in ages likely occurred between the analyses of younger and older women.

In postmenopausal women younger than 60, the total mortality rate was reduced by 39% in women taking estrogen-containing hormone therapy, which was significant; in women older than 60, there was no significant effect on total mortality.

The data were from 30 randomized, controlled clinical trials published between 1966 and 2002, and included 26,708 women taking estrogen (ET) or estrogen plus progestogen (EPT). Data were pooled to determine total mortality and mortality due to specific causes such as cardiovascular disease and cancer. The mean trial duration was 4.5 years, and the mean age was 62.2 years.

When the study population was divided into younger and older age groups based on mean ages, it was found that those younger than 60 (mean age, 53.9) had a significantly reduced OR for total mortality of 0.61 (95% CI, 0.39–0.95) and those older than age 60 (mean age, 64.6) had an OR of 1.03 (95% CI, 0.90–1.18).

For specific causes, the OR for cardiovascular disease mortality associated with ET/EPT was 1.10 (95% CI, 0.90–1.34). For overall cancer mortality, the OR was 1.03 (95% CI, 0.82–1.29) and for breast cancer mortality, the OR was 1.03 (95% CI, 0.29–3.67).

For causes other than cardiovascular disease or cancer, mortality was significantly lower in women on HT: OR 0.67 (95% CI, 0.51–0.88). When divided into younger and older age groups, ET/EPT was not associated with a significant change in mortality, with the exception of reduced mortality from causes other than cardiovascular disease and cancer in the older age group (OR, 0.68; 95% CI, 0.56–0.91).

Does HT improve insulin resistance?

Margolis KL, Bonds DE, Rodabough RJ, et al, for the Women’s Health Initiative Investigators. Effect of oestrogen plus progestin on the incidence of diabetes in postmenopausal women: results from the Women’s Health Initiative Hormone Trial. Diabetologia. 2004;47:1175–1187. LEVEL 1 EVIDENCE: Randomized, controlled trial

Hormone therapy, compared with placebo, was associated with 15 fewer cases of diabetes per 10,000 women per year. Fasting glucose and insulin decreased compared with placebo, and may suggest improved insulin resistance. Although others have reported similar results, it is unlikely that hormone therapy will be prescribed to prevent diabetes, given its greater risk than benefit for other outcomes observed in other WHI analyses.

In the EPT part of WHI, a total of 15,641 postmenopausal women aged 50 to 79 were assigned to placebo or continuous-combined EPT (0.625 mg/day conjugated equine estrogens plus 2.5 mg/day medroxyprogesterone acetate). The incidence of diabetes was based on self-reports of insulin or oral diabetes drug treatment. Fasting glucose, insulin, and lipoproteins were measured at 1 and 3 years. After 5.6 years, the incidence of treated diabetes was 3.5% in the EPT group and 4.2% in the placebo group (hazard ratio, 0.79; 95% CI, 0.67–0.93; P= 0.004). Decreases in fasting glucose and insulin, suggesting decreased insulin resistance, were significant at 1 year in EPT users compared with placebo. The authors concluded that EPT reduces the incidence of diabetes possibly through a decrease in insulin resistance.

To be sure that a drug prevents a disease, everyone with the disease should be excluded at baseline, and at the end of the trial, everyone should be tested for the disease—if it is commonly undiagnosed. To study the incidence of new diabetes, all women (6%) with self-reported diabetes at baseline were excluded, and correctly so. But half of US adults with diabetes are undiagnosed. The WHI 6% prevalence is half of the assumed 12% prevalence in older overweight women. In the WHI, average age was 63 years and average body mass index was 28. Thus, it is not certain that the reduced risk occurred in women who were diabetes-free at baseline.

Fasting glucose was reduced in the EPT part of WHI, as in the Postmenopausal Estrogen Progestin Intervention (PEPI) trial. But 2-hour glucose levels were elevated by hormone treatment in PEPI, and were not measured in the WHI. Many studies have shown that postprandial or post-challenge glucose is a stronger risk factor for cardiovascular disease than fasting hyperglycemia.

Could an elevated post-challenge glucose have played a role in the unexpected excess cardiovascular disease observed with hormone therapy in healthy women in WHI and with hormone therapy in women with documented coronary heart disease in the Heart and Estrogen/progestin Replacement Study (HERS)?

Will transdermal estrogen reduce both fasting and post-challenge glucose? These and other questions remain. (EBC)

Lifestyle changes work best

• This report raises the possibility but does not justify prescribing EPT for diabetes prevention.

Postmenopausal women randomized to EPT had a lower incidence of treated diabetes, by self-report, than women assigned to placebo: a 21% relative risk reduction over 3 years. At 1 year, a comparison of changes from baseline in estimated insulin resistance (HOMA model) in a subgroup indicated a significant reduction with EPT compared with placebo group, but no significant difference at 3 years.

Because of the far-reaching morbidity and mortality due to Type 2 diabetes, particularly from cardiovascular disease, prevention would have major benefits, but the authors acknowledge that this report does not justify prescribing this therapy for this purpose, given hazards previously reported in the WHI.

Still, we can bear in mind other means of reducing risk for diabetes. In the Diabetes Prevention Program,¹metformin reduced type 2 diabetes risk by 31%, and a diet plus exercise program reduced it even more: by 58% over approximately 3 years of follow-up in high-risk persons. People at risk for diabetes should be counseled to make lifestyle changes that can reduce this risk far more, and more safely, than might EPT. (CGS)

Consider diabetes implications

• EPT can reduce the incidence of diabetes to the same degree as medications used for cardiovascular disease prevention.²

Growing evidence indicates that reducing insulin resistance in women can prevent onset of diabetes,³and that improving insulin resistance can slow the progression of atherosclerosis.⁴ Observational studies⁵—the Heart and Estrogen/progestin Replacement Study (HERS),⁶ and now the WHI—strongly indicate that EPT reduces the incidence of diabetes in postmenopausal women. Notably, HERS and WHI findings were with continuous-combined estrogen with progestin, the latter often viewed as antagonistic to the beneficial effects of estrogen on carbohydrate metabolism.) Diabetes is much more devastating in women, and more likely to strike. The risk (3,000 of 10,000) in postmenopausal women equals or exceeds that of postmenopausal breast cancer, coronary disease, or hip fracture.⁷The time has come to consider health and cost implications of long-term HT, especially in women with diabetes risk factors: age, obesity, high systolic BP, high nonfasting glucose, antihypertensive drug use, low HDL, or Hispanic or African-American ethnicity. Clinical trials confirming HT’s benefit add to the totality of evidence that the benefits outweigh the risks.⁸Since long-term effects (>10 years) reflect only observational data, we urgently need studies designed to understand long-term benefits and risks. (HNH)

1. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346:393-403.

2. Pepine CJ, Cooper-Dehoff RM. Cardiovascular therapies and risk for development of diabetes. J Am Coll Cardiol. 2004;44:509-512.

3. Buchanan TA, Xiang AH, Peters RK, et al. Preservation of pancreatic beta-cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance inhigh risk Hispanic women. Diabetes. 2002;51:2796-2803.

4. Xiang AH, Peters RK, Kjos SL, et al. Effect of thiazolidinedione treatment on progression of subclinical atherosclerosis in premenopausal women at high risk for type 2 diabetes. J Clin Endocrinol Metab. 2005;90:1986-1991.

5. Manson JE, Rimm EB, Colditz GA, et al. A prospective study of postmenopausal estrogen therapy and subsequent incidence of non-insulin-dependent diabetes mellitus. Ann Epidemiol. 1992;2:665-673.

6. Kanaya AM, Herrington D, et al. Glycemic effects of postmenopausal hormone therapy: Heart and Estrogen/progestin Replacement Study. Randomized, double-blind, placebo-controlled trial. Ann Intern Med. 2003;138:1-9.

7. Narayan KMV, Boyle JP, et al. Lifetime risk for diabetes mellitus in the US. JAMA 2003;290:1884-1890.

8. Philips LS, Langer RD. Postmenopausal hormone therapy: critical reappraisal and a unified hypothesis. Fertil Steril. 2005;83:558-566.

Soy versus placebo: Underwhelming

Red clover, likewise

Trebs EE, Ensrud KE, MacDonald R, Wilt TJ. Phytoestrogens for treatment of menopausal symptoms: a systematic review. Obstet Gynecol. 2004;104:824–836. META-ANALYSIS

Data on 2,348 women (mean age, 53.1 years) experiencing a mean of 7.1 hot flashes per week were analyzed. Only randomized controlled trials reporting menopausal symptoms of hot flashes, night sweats, and vaginal dryness were included. Mean trial duration was 17 weeks.

• The 11 soy food or beverage supplementtrials (N = 995 women) found no improvement compared with placebo.
• Of the 8 soy food trialsreporting hot flash outcomes, only 1 showed a significant improvement compared with placebo.
• In the 9 soy extract trials, overall results (N = 854) were mixed. In 5 trials using soy extracts and reporting hot flash frequency, 3 found no significant difference in symptoms between the soy and placebo groups; the other 2 (total 114 subjects) found significant improvements.
• The 5 red clover trials(N = 400) showed no improvement over placebo.

Many women in these studies appear to have been perimenopausal rather than postmenopausal. Nine studies included women who had had a menstrual period within the previous 3 to 6 months (late perimenopausal). A subgroup analysis of perimenopausal women would have been useful, since their endocrinologic status is quite different from that of postmenopausal women.

Does soy improve cognition, bone density, or lipids?

Kreijkamp-Kaspers S, Kok L, Grobbee DE, et al. Effect of soy protein containing isoflavones on cognitive function, bone mineral density, and plasma lipids in postmenopausal women: a randomized controlled trial. JAMA. 2004;292:65–74. LEVEL 1 EVIDENCE: Randomized, controlled trial

This careful trial raises the question of how to reconcile these results with animal and observational studies. In all, 202 postmenopausal women aged 60 to 75 years received 25.6 g/day of a soy protein supplement containing 99 mg isoflavones or a milk protein powder for 1 year. Adherence was monitored by serum genistein. There were no notable differences in:

• Memory, verbal skills, or concentration.
• Bone mineral density or bone-specific alkaline phosphatase, calcium, or phosphorus levels.
• Cholesterol, triglycerides, and lipoprotein plasma levels. These findings may not relate to perimenopausal women, in whom soy has been seen to significantly reduce LDL, but only during midfollicular and periovulatory phases.¹ Premenopausal² but not postmenopausal³monkeys given soy have had beneficial effects on bone quality.

REFERENCES

1. Merz-Demlow BE, Duncan AM, Wangen KE, et al. Soy isoflavones improve plasma lipids in normocholes-terolemic, premenopausal women. Am J Clin Nutr. 2000;71:1462-1469.

2. Kaplan JR, et al. Supplementation reduces the trajectory of atherogenesis in premenopausal monkeys at high risk for development of extensive postmenopausal coronary artery plaques. Menopause. 2004;11:653. Abstract S-17.

3. Register TC, Jayo MJ, Anthony MS. Soy phytoestrogens do not prevent bone loss in postmenopausal monkeys. J Clin Endocrinol Metab. 2003;88:4362-4370.

LIFESTYLE THERAPYThe secret to keeping those girlish carotids

Wildman RP, Schott LL, Brockwell S, Kuller LH, Sutton-Tyrrell K. A dietary and exercise intervention slows menopause-associated progression of subclinical atherosclerosis as measured by intima-media thickness of the carotid arteries. J Am Coll Cardiol. 2004;44:579–585. LEVEL 1 EVIDENCE: Randomized, controlled trial

These important findings are strong evidence that diet and exercise can slow the subclinical atherosclerosis progression that accompanies the menopause transition.

The Women’s Healthy Lifestyle Project previously found that weight gain and increased lipids, glucose, and blood pressure often accompany the menopause transition.¹ This report describes improvements with diet and exercise intervention, compared with controls.

A total of 535 women aged 44 to 50 years were randomized to lifestyle intervention or assessment-only. All were premenopausal, and all had normal to high-normal body mass index, diastolic blood pressure, and fasting glucose and cholesterol levels.

The diet and exercise regimen used in the study was designed to reduce fat and cholesterol, prevent weight gain, and increase physical activity.

End points were progression of intimamedia thickness in the common carotid artery, internal carotid artery, and bulb segments.

The control group had significantly greater increases in intima-media thickness in women who became postmenopausal compared with those who remained premenopausal.

For women who became perimenopausal or postmenopausal during this 4-year study, diet and exercise slowed the progression of intima-media thickness by a 47% average reduction (P< 0.05), but had no effect on carotid segments in the women who remained premenopausal.

No benefit in intima media thickness was seen in women who remained premenopausal during the trial. Nevertheless, there are many well-documented benefits of healthy diet and exercise in premenopausal women.

Also of note, hormone therapy initiated after baseline measurements did not alter the results.

The message for patients, especially perimenopausal patients is that there is no time like the present to start a healthy lifestyle.

No downside

We’ve learned from the Nurse’s Health Study,²an observational study, that women who eat a healthy diet, do not smoke, and who exercise can reduce their risk of coronary heart disease by 57%.

We learned from the randomized controlled trial by the Diabetes Prevention Program Research Group³ that diet and exercise in high-risk women for 3 years can reduce incidence of new diabetes by 58%.

Now, in this trial, we learn that diet and exercise can reduce the progression of atherosclerosis in perimenopausal women by nearly 50%.

Since there is little, if any, downside to healthy living, why wait?

Dr. Utian has served as an advisor/consultant for Eli Lilly, Pfizer, and Novartis. He has received research funding from Amylin, 3m, Barr, Berlex, BMS, Eli Lilly, Forest, Galen, Glaxo Smith Kline, Neurocrine Biosciences, Novartis, Novo Nordisk, Organon, Pharmacia, P&G, Pfizer, Roche, Sepracor, Solvay, Wyeth, and Yamanouchi.

Dr. Ettinger has served as an advisor for Berlex, Duramed-Barr, Glaxo Smith Kline, and P&G.

REFERENCES

1. Kuller LH, Simkin-Silverman LR, Wing RR, Meilahn EN, Ives DG. Women’s Healthy Lifestyle Project: a randomized clinical trial: results at 54 months. Circulation. 2001;103:32-37.

2. Stampfer MJ, Hu FB, Manson JE, Rimm EB, Willett WC. Primary prevention of coronary heart disease in women through diet and lifestyle. N Engl J Med. 2000;343:16-22.

3. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346:393-403.

Time and study make a difference. So does careful review and reappraisal of existing data. In the past year, the pendulum has swung away from fear of hormone therapy to a better understanding of indications, risks and benefits—an understanding driven largely by the evidence-based position statements of the North American Menopause Society (NAMS).

A meta-analysis of randomized controlled trials of phytoestrogens attested to lack of efficacy or weak effect, which helps clear the picture on soy and red clover, but the researchers stressed that the lack of quality control does not rule out the possibility that some products might carry steroidal effects and potential risk.

And another year has brought even more evidence that diet, exercise, smoking cessation and the like really do improve health and quality of life.

Advisory on hormone therapy and “bio-identicals”

The NAMS Hormone Therapy Panel concluded definitively that bio-identical hormones should be considered in the same category as all the sex steroids, which, in the absence of specific safety and efficacy studies, carry the same risks and benefits as related products.

On the other hand, alternatives do exist for specific indications, such as bisphosphonates for bone conservation.

The new NAMSPosition Statement stresses individualized treatment based on the recommendations below.

The full report is available at www.menopause.org.

• Treatment of moderate to severe menopausal symptoms is the primary indications for systemic therapy. Every systemic product is FDA-approved for this indication.
• Every systemic and local product is approved for moderate vulvar and vaginal atrophy. For this indication alone, local ET is generally advised.
• Duration should be for the lowest effective dose and shortest time consistent with treatment goals.
• If the woman is well aware of potential risks and benefits, and if there is clinical supervision, extended use of the lowest effective ET/EPT dose for treatment goals is acceptable in women who believe the benefits outweigh the risks, for those at high risk of osteoporotic fracture who also have moderate to severe menopause symptoms, for further prevention of established bone loss when alternate therapies are not appropriate or cause side effects, or when outcomes of extended use of those therapies are not known.
• Although specific compounds, doses, and routes of administration may have different outcomes, clinical trial results for one agent should be generalized to all agents within the same family in the absence of data for each specific product. This proviso also applies to the so-called bioidentical products.

Question marks

The Hormone Therapy panel could not agree unanimously on these questions:

• Should women who are doing well on long-term HT discontinue?
• What is the best way to discontinue HT, abrupt cessation or tapering?
• Is the effect of continuous-combined EPT different from that of continuous estrogen with sequential progestogen?
• How definitive is the evidence on early increased CHD risk with HT?
• Conflicting data precluded a consensus on adverse breast cancer and cardiovascular outcomes associated with ET/EPT.

ACKNOWLEDGMENTS

The following commentaries on key papers are from the NAMS First To Knowemail program for members. I thank the members of NAMS who have taken time out to provide these objective reviews of the studies presented here, and Phil Lammers, NAMS Medical Editor.

OSTEOPOROSISCurb your enthusiasm—no need to rush bone drugs if risk is low

McClung MR, Wasnich RD, Hosking DJ, et al, on behalf of the Early Postmenopausal Intervention Cohort (EPIC) study group. Prevention of postmenopausal bone loss: six-year results from the early postmenopausal intervention cohort study. J Clin Endocrinol Metab 2004;89:4879-4885. LEVEL 1 EVIDENCE: Randomized, controlled trial

Women in their 50s are not melting away. Their bones are not dissolving out from under them, contrary to what many media reports would have ObGyns and patients believe. Still, many clinicians are enthusiastic about prescribing bone drugs like bisphosphonates to women in their 50s who are generally healthy. (And there is no doubt that we do have bone drugs found to be safe and effective in well-designed trials, including the EPIC study.)

Yet there has been a major shift away from starting osteoporosis prevention drugs soon after menopause. EPIC data add support for a “go slow” strategy for drug intervention in healthy women in their 50s.

The EPIC study involved a total of 1,609 women ages 45 to 59, who received alendronate or placebo in a double-blind, randomized design. BMD was measured annually. The 4-year results were reported previously, and the 6-year results were published just last fall. Not surprisingly, women using alendronate had some increase in BMD and some reduction in bone turnover markers. But the results in the women who took placebo are of singular interest.

After 6 years, women on placebo had lost very little bone. The amount lost was statistically significant, but clinically inconsequential. The average BMD in women on placebo decreased 3% in the spine and 2% in the hip. Thus, the average rate of bone loss was about 0.5% per year.

A bone mass decrease of this extent represents a decline of about -0.3 T score, which is negligible. In the EPIC study, the 6-year fracture benefit, based on any type of fracture, boils down to lowering the risk from 1 in 11 on placebo to 1 in 9 on alendronate. These healthy women in their 50s had a very low risk of fracture, and taking a drug for 6 years had very little benefit for fracture reduction.

Women in their 50s typically have about 10% to 15% less bone mass than women of 25 to 30, when bone mass is at its peak. That 10% to 15% lower BMD translates to a T score of –1 to –1.2 , which is currently being labeled as osteopenic. Many patients and physicians have come to feel that osteopenia must always be treated with our newer drugs.

We are discovering that starting healthy women in their 50s on osteoporosis prevention drugs carries an extremely high cost per fracture avoided. During the 10 years since the startup of the EPIC study, support for early drug intervention in healthy women still in their 50s has dwindled. Now, expert groups, including the National Osteoporosis Foundation and the US Preventive Services Task Force, advise waiting until age 65 before starting osteoporosis risk evaluation or considering drug intervention in women who are otherwise healthy.

In my practice, I give healthy women in their 50s permission not to take drugs if their risk of fracture within the next 5 to 10 years is low. The picture is quite different in postmenopausal women in their 50s who do have high fracture risk, such as those who have already had a fracture, or who have very low bone density or high exposure to glucocorticoids.

EPIC data support the concept that the rate of bone loss is quite slow after a year or 2 has elapsed after menopause.

We need to avoid medicalizing these patients simply because we have drugs that reduce bone loss or because women in their 50s have less bone mass than 25-year-olds.

BIBLIOGRAPHY

Hosking D, Chilvers CE, Christiansen C, et al. Prevention of bone loss with alendronate in postmenopausal women under 60 years of age. Early Postmenopausal Intervention Cohort Study Group. N Engl J Med. 1998;338:485-492.

Wasnich RD, Bagger YZ, Hosking DJ, et al. Changes in bone density and turnover after alendronate or estrogen withdrawal. Menopause. 2004;11:622-630.

Siris ES, Bilezikian JP, Rubin MR, et al. Pins and plasters aren’t enough: a call for the evaluation and treatment of patients with osteoporotic fractures. J Clin Endocrinol Metab. 2003;88:3482-3486.

Rosen CJ, Black DM, Greenspan SL. Vignettes in osteoporosis: a road map to successful therapeutics. J Bone Miner Res. 2004;19:3-10.

HORMONE THERAPYDoes age affect mortality rate in postmenopausal women using HT?

Salpeter SR, Walsh JME, Greyber E, Ormiston TM, Salpeter EE. Mortality associated with hormone replacement therapy in younger and older women. J Gen Intern Med. 2004;19:791–804. META-ANALYSIS

This study attempted to discover whether the age of the postmenopausal woman using hormone therapy affects mortality. Investigators performed a meta-analysis of clinical trials that reported mortality rates associated with use of postmenopausal hormone therapy, and analyzed the results based on mean ages.

They reported a significant trend between increasing risk of mortality and increasing mean age of the women using hormone therapy—raising the possibility of a health benefit for younger postmenopausal women.

The studies included in the metaanalysis varied in entry criteria, outcomes assessed, number of subjects, and HT type and dosage. Furthermore, because age groups were defined by mean age in each trial rather than actual age of pooled participants, some overlap in ages likely occurred between the analyses of younger and older women.

In postmenopausal women younger than 60, the total mortality rate was reduced by 39% in women taking estrogen-containing hormone therapy, which was significant; in women older than 60, there was no significant effect on total mortality.

The data were from 30 randomized, controlled clinical trials published between 1966 and 2002, and included 26,708 women taking estrogen (ET) or estrogen plus progestogen (EPT). Data were pooled to determine total mortality and mortality due to specific causes such as cardiovascular disease and cancer. The mean trial duration was 4.5 years, and the mean age was 62.2 years.

When the study population was divided into younger and older age groups based on mean ages, it was found that those younger than 60 (mean age, 53.9) had a significantly reduced OR for total mortality of 0.61 (95% CI, 0.39–0.95) and those older than age 60 (mean age, 64.6) had an OR of 1.03 (95% CI, 0.90–1.18).

For specific causes, the OR for cardiovascular disease mortality associated with ET/EPT was 1.10 (95% CI, 0.90–1.34). For overall cancer mortality, the OR was 1.03 (95% CI, 0.82–1.29) and for breast cancer mortality, the OR was 1.03 (95% CI, 0.29–3.67).

For causes other than cardiovascular disease or cancer, mortality was significantly lower in women on HT: OR 0.67 (95% CI, 0.51–0.88). When divided into younger and older age groups, ET/EPT was not associated with a significant change in mortality, with the exception of reduced mortality from causes other than cardiovascular disease and cancer in the older age group (OR, 0.68; 95% CI, 0.56–0.91).

Does HT improve insulin resistance?

Margolis KL, Bonds DE, Rodabough RJ, et al, for the Women’s Health Initiative Investigators. Effect of oestrogen plus progestin on the incidence of diabetes in postmenopausal women: results from the Women’s Health Initiative Hormone Trial. Diabetologia. 2004;47:1175–1187. LEVEL 1 EVIDENCE: Randomized, controlled trial

Hormone therapy, compared with placebo, was associated with 15 fewer cases of diabetes per 10,000 women per year. Fasting glucose and insulin decreased compared with placebo, and may suggest improved insulin resistance. Although others have reported similar results, it is unlikely that hormone therapy will be prescribed to prevent diabetes, given its greater risk than benefit for other outcomes observed in other WHI analyses.

In the EPT part of WHI, a total of 15,641 postmenopausal women aged 50 to 79 were assigned to placebo or continuous-combined EPT (0.625 mg/day conjugated equine estrogens plus 2.5 mg/day medroxyprogesterone acetate). The incidence of diabetes was based on self-reports of insulin or oral diabetes drug treatment. Fasting glucose, insulin, and lipoproteins were measured at 1 and 3 years. After 5.6 years, the incidence of treated diabetes was 3.5% in the EPT group and 4.2% in the placebo group (hazard ratio, 0.79; 95% CI, 0.67–0.93; P= 0.004). Decreases in fasting glucose and insulin, suggesting decreased insulin resistance, were significant at 1 year in EPT users compared with placebo. The authors concluded that EPT reduces the incidence of diabetes possibly through a decrease in insulin resistance.

To be sure that a drug prevents a disease, everyone with the disease should be excluded at baseline, and at the end of the trial, everyone should be tested for the disease—if it is commonly undiagnosed. To study the incidence of new diabetes, all women (6%) with self-reported diabetes at baseline were excluded, and correctly so. But half of US adults with diabetes are undiagnosed. The WHI 6% prevalence is half of the assumed 12% prevalence in older overweight women. In the WHI, average age was 63 years and average body mass index was 28. Thus, it is not certain that the reduced risk occurred in women who were diabetes-free at baseline.

Fasting glucose was reduced in the EPT part of WHI, as in the Postmenopausal Estrogen Progestin Intervention (PEPI) trial. But 2-hour glucose levels were elevated by hormone treatment in PEPI, and were not measured in the WHI. Many studies have shown that postprandial or post-challenge glucose is a stronger risk factor for cardiovascular disease than fasting hyperglycemia.

Could an elevated post-challenge glucose have played a role in the unexpected excess cardiovascular disease observed with hormone therapy in healthy women in WHI and with hormone therapy in women with documented coronary heart disease in the Heart and Estrogen/progestin Replacement Study (HERS)?

Will transdermal estrogen reduce both fasting and post-challenge glucose? These and other questions remain. (EBC)

Lifestyle changes work best

• This report raises the possibility but does not justify prescribing EPT for diabetes prevention.

Postmenopausal women randomized to EPT had a lower incidence of treated diabetes, by self-report, than women assigned to placebo: a 21% relative risk reduction over 3 years. At 1 year, a comparison of changes from baseline in estimated insulin resistance (HOMA model) in a subgroup indicated a significant reduction with EPT compared with placebo group, but no significant difference at 3 years.

Because of the far-reaching morbidity and mortality due to Type 2 diabetes, particularly from cardiovascular disease, prevention would have major benefits, but the authors acknowledge that this report does not justify prescribing this therapy for this purpose, given hazards previously reported in the WHI.

Still, we can bear in mind other means of reducing risk for diabetes. In the Diabetes Prevention Program,¹metformin reduced type 2 diabetes risk by 31%, and a diet plus exercise program reduced it even more: by 58% over approximately 3 years of follow-up in high-risk persons. People at risk for diabetes should be counseled to make lifestyle changes that can reduce this risk far more, and more safely, than might EPT. (CGS)

Consider diabetes implications

• EPT can reduce the incidence of diabetes to the same degree as medications used for cardiovascular disease prevention.²

Growing evidence indicates that reducing insulin resistance in women can prevent onset of diabetes,³and that improving insulin resistance can slow the progression of atherosclerosis.⁴ Observational studies⁵—the Heart and Estrogen/progestin Replacement Study (HERS),⁶ and now the WHI—strongly indicate that EPT reduces the incidence of diabetes in postmenopausal women. Notably, HERS and WHI findings were with continuous-combined estrogen with progestin, the latter often viewed as antagonistic to the beneficial effects of estrogen on carbohydrate metabolism.) Diabetes is much more devastating in women, and more likely to strike. The risk (3,000 of 10,000) in postmenopausal women equals or exceeds that of postmenopausal breast cancer, coronary disease, or hip fracture.⁷The time has come to consider health and cost implications of long-term HT, especially in women with diabetes risk factors: age, obesity, high systolic BP, high nonfasting glucose, antihypertensive drug use, low HDL, or Hispanic or African-American ethnicity. Clinical trials confirming HT’s benefit add to the totality of evidence that the benefits outweigh the risks.⁸Since long-term effects (>10 years) reflect only observational data, we urgently need studies designed to understand long-term benefits and risks. (HNH)

1. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346:393-403.

2. Pepine CJ, Cooper-Dehoff RM. Cardiovascular therapies and risk for development of diabetes. J Am Coll Cardiol. 2004;44:509-512.

3. Buchanan TA, Xiang AH, Peters RK, et al. Preservation of pancreatic beta-cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance inhigh risk Hispanic women. Diabetes. 2002;51:2796-2803.

4. Xiang AH, Peters RK, Kjos SL, et al. Effect of thiazolidinedione treatment on progression of subclinical atherosclerosis in premenopausal women at high risk for type 2 diabetes. J Clin Endocrinol Metab. 2005;90:1986-1991.

5. Manson JE, Rimm EB, Colditz GA, et al. A prospective study of postmenopausal estrogen therapy and subsequent incidence of non-insulin-dependent diabetes mellitus. Ann Epidemiol. 1992;2:665-673.

6. Kanaya AM, Herrington D, et al. Glycemic effects of postmenopausal hormone therapy: Heart and Estrogen/progestin Replacement Study. Randomized, double-blind, placebo-controlled trial. Ann Intern Med. 2003;138:1-9.

7. Narayan KMV, Boyle JP, et al. Lifetime risk for diabetes mellitus in the US. JAMA 2003;290:1884-1890.

8. Philips LS, Langer RD. Postmenopausal hormone therapy: critical reappraisal and a unified hypothesis. Fertil Steril. 2005;83:558-566.

Soy versus placebo: Underwhelming

Red clover, likewise

Trebs EE, Ensrud KE, MacDonald R, Wilt TJ. Phytoestrogens for treatment of menopausal symptoms: a systematic review. Obstet Gynecol. 2004;104:824–836. META-ANALYSIS

Data on 2,348 women (mean age, 53.1 years) experiencing a mean of 7.1 hot flashes per week were analyzed. Only randomized controlled trials reporting menopausal symptoms of hot flashes, night sweats, and vaginal dryness were included. Mean trial duration was 17 weeks.

• The 11 soy food or beverage supplementtrials (N = 995 women) found no improvement compared with placebo.
• Of the 8 soy food trialsreporting hot flash outcomes, only 1 showed a significant improvement compared with placebo.
• In the 9 soy extract trials, overall results (N = 854) were mixed. In 5 trials using soy extracts and reporting hot flash frequency, 3 found no significant difference in symptoms between the soy and placebo groups; the other 2 (total 114 subjects) found significant improvements.
• The 5 red clover trials(N = 400) showed no improvement over placebo.

Many women in these studies appear to have been perimenopausal rather than postmenopausal. Nine studies included women who had had a menstrual period within the previous 3 to 6 months (late perimenopausal). A subgroup analysis of perimenopausal women would have been useful, since their endocrinologic status is quite different from that of postmenopausal women.

Does soy improve cognition, bone density, or lipids?

Kreijkamp-Kaspers S, Kok L, Grobbee DE, et al. Effect of soy protein containing isoflavones on cognitive function, bone mineral density, and plasma lipids in postmenopausal women: a randomized controlled trial. JAMA. 2004;292:65–74. LEVEL 1 EVIDENCE: Randomized, controlled trial

This careful trial raises the question of how to reconcile these results with animal and observational studies. In all, 202 postmenopausal women aged 60 to 75 years received 25.6 g/day of a soy protein supplement containing 99 mg isoflavones or a milk protein powder for 1 year. Adherence was monitored by serum genistein. There were no notable differences in:

• Memory, verbal skills, or concentration.
• Bone mineral density or bone-specific alkaline phosphatase, calcium, or phosphorus levels.
• Cholesterol, triglycerides, and lipoprotein plasma levels. These findings may not relate to perimenopausal women, in whom soy has been seen to significantly reduce LDL, but only during midfollicular and periovulatory phases.¹ Premenopausal² but not postmenopausal³monkeys given soy have had beneficial effects on bone quality.

REFERENCES

1. Merz-Demlow BE, Duncan AM, Wangen KE, et al. Soy isoflavones improve plasma lipids in normocholes-terolemic, premenopausal women. Am J Clin Nutr. 2000;71:1462-1469.

2. Kaplan JR, et al. Supplementation reduces the trajectory of atherogenesis in premenopausal monkeys at high risk for development of extensive postmenopausal coronary artery plaques. Menopause. 2004;11:653. Abstract S-17.

3. Register TC, Jayo MJ, Anthony MS. Soy phytoestrogens do not prevent bone loss in postmenopausal monkeys. J Clin Endocrinol Metab. 2003;88:4362-4370.

LIFESTYLE THERAPYThe secret to keeping those girlish carotids

Wildman RP, Schott LL, Brockwell S, Kuller LH, Sutton-Tyrrell K. A dietary and exercise intervention slows menopause-associated progression of subclinical atherosclerosis as measured by intima-media thickness of the carotid arteries. J Am Coll Cardiol. 2004;44:579–585. LEVEL 1 EVIDENCE: Randomized, controlled trial

These important findings are strong evidence that diet and exercise can slow the subclinical atherosclerosis progression that accompanies the menopause transition.

The Women’s Healthy Lifestyle Project previously found that weight gain and increased lipids, glucose, and blood pressure often accompany the menopause transition.¹ This report describes improvements with diet and exercise intervention, compared with controls.

A total of 535 women aged 44 to 50 years were randomized to lifestyle intervention or assessment-only. All were premenopausal, and all had normal to high-normal body mass index, diastolic blood pressure, and fasting glucose and cholesterol levels.

The diet and exercise regimen used in the study was designed to reduce fat and cholesterol, prevent weight gain, and increase physical activity.

End points were progression of intimamedia thickness in the common carotid artery, internal carotid artery, and bulb segments.

The control group had significantly greater increases in intima-media thickness in women who became postmenopausal compared with those who remained premenopausal.

For women who became perimenopausal or postmenopausal during this 4-year study, diet and exercise slowed the progression of intima-media thickness by a 47% average reduction (P< 0.05), but had no effect on carotid segments in the women who remained premenopausal.

No benefit in intima media thickness was seen in women who remained premenopausal during the trial. Nevertheless, there are many well-documented benefits of healthy diet and exercise in premenopausal women.

Also of note, hormone therapy initiated after baseline measurements did not alter the results.

The message for patients, especially perimenopausal patients is that there is no time like the present to start a healthy lifestyle.

No downside

We’ve learned from the Nurse’s Health Study,²an observational study, that women who eat a healthy diet, do not smoke, and who exercise can reduce their risk of coronary heart disease by 57%.

We learned from the randomized controlled trial by the Diabetes Prevention Program Research Group³ that diet and exercise in high-risk women for 3 years can reduce incidence of new diabetes by 58%.

Now, in this trial, we learn that diet and exercise can reduce the progression of atherosclerosis in perimenopausal women by nearly 50%.

Since there is little, if any, downside to healthy living, why wait?

Dr. Utian has served as an advisor/consultant for Eli Lilly, Pfizer, and Novartis. He has received research funding from Amylin, 3m, Barr, Berlex, BMS, Eli Lilly, Forest, Galen, Glaxo Smith Kline, Neurocrine Biosciences, Novartis, Novo Nordisk, Organon, Pharmacia, P&G, Pfizer, Roche, Sepracor, Solvay, Wyeth, and Yamanouchi.

Dr. Ettinger has served as an advisor for Berlex, Duramed-Barr, Glaxo Smith Kline, and P&G.

REFERENCES

1. Kuller LH, Simkin-Silverman LR, Wing RR, Meilahn EN, Ives DG. Women’s Healthy Lifestyle Project: a randomized clinical trial: results at 54 months. Circulation. 2001;103:32-37.

2. Stampfer MJ, Hu FB, Manson JE, Rimm EB, Willett WC. Primary prevention of coronary heart disease in women through diet and lifestyle. N Engl J Med. 2000;343:16-22.

3. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346:393-403.

Time and study make a difference. So does careful review and reappraisal of existing data. In the past year, the pendulum has swung away from fear of hormone therapy to a better understanding of indications, risks and benefits—an understanding driven largely by the evidence-based position statements of the North American Menopause Society (NAMS).

A meta-analysis of randomized controlled trials of phytoestrogens attested to lack of efficacy or weak effect, which helps clear the picture on soy and red clover, but the researchers stressed that the lack of quality control does not rule out the possibility that some products might carry steroidal effects and potential risk.

And another year has brought even more evidence that diet, exercise, smoking cessation and the like really do improve health and quality of life.

Advisory on hormone therapy and “bio-identicals”

The NAMS Hormone Therapy Panel concluded definitively that bio-identical hormones should be considered in the same category as all the sex steroids, which, in the absence of specific safety and efficacy studies, carry the same risks and benefits as related products.

On the other hand, alternatives do exist for specific indications, such as bisphosphonates for bone conservation.

The new NAMSPosition Statement stresses individualized treatment based on the recommendations below.

The full report is available at www.menopause.org.

• Treatment of moderate to severe menopausal symptoms is the primary indications for systemic therapy. Every systemic product is FDA-approved for this indication.
• Every systemic and local product is approved for moderate vulvar and vaginal atrophy. For this indication alone, local ET is generally advised.
• Duration should be for the lowest effective dose and shortest time consistent with treatment goals.
• If the woman is well aware of potential risks and benefits, and if there is clinical supervision, extended use of the lowest effective ET/EPT dose for treatment goals is acceptable in women who believe the benefits outweigh the risks, for those at high risk of osteoporotic fracture who also have moderate to severe menopause symptoms, for further prevention of established bone loss when alternate therapies are not appropriate or cause side effects, or when outcomes of extended use of those therapies are not known.
• Although specific compounds, doses, and routes of administration may have different outcomes, clinical trial results for one agent should be generalized to all agents within the same family in the absence of data for each specific product. This proviso also applies to the so-called bioidentical products.

Question marks

The Hormone Therapy panel could not agree unanimously on these questions:

• Should women who are doing well on long-term HT discontinue?
• What is the best way to discontinue HT, abrupt cessation or tapering?
• Is the effect of continuous-combined EPT different from that of continuous estrogen with sequential progestogen?
• How definitive is the evidence on early increased CHD risk with HT?
• Conflicting data precluded a consensus on adverse breast cancer and cardiovascular outcomes associated with ET/EPT.

ACKNOWLEDGMENTS

The following commentaries on key papers are from the NAMS First To Knowemail program for members. I thank the members of NAMS who have taken time out to provide these objective reviews of the studies presented here, and Phil Lammers, NAMS Medical Editor.

OSTEOPOROSISCurb your enthusiasm—no need to rush bone drugs if risk is low

McClung MR, Wasnich RD, Hosking DJ, et al, on behalf of the Early Postmenopausal Intervention Cohort (EPIC) study group. Prevention of postmenopausal bone loss: six-year results from the early postmenopausal intervention cohort study. J Clin Endocrinol Metab 2004;89:4879-4885. LEVEL 1 EVIDENCE: Randomized, controlled trial

Women in their 50s are not melting away. Their bones are not dissolving out from under them, contrary to what many media reports would have ObGyns and patients believe. Still, many clinicians are enthusiastic about prescribing bone drugs like bisphosphonates to women in their 50s who are generally healthy. (And there is no doubt that we do have bone drugs found to be safe and effective in well-designed trials, including the EPIC study.)

Yet there has been a major shift away from starting osteoporosis prevention drugs soon after menopause. EPIC data add support for a “go slow” strategy for drug intervention in healthy women in their 50s.

The EPIC study involved a total of 1,609 women ages 45 to 59, who received alendronate or placebo in a double-blind, randomized design. BMD was measured annually. The 4-year results were reported previously, and the 6-year results were published just last fall. Not surprisingly, women using alendronate had some increase in BMD and some reduction in bone turnover markers. But the results in the women who took placebo are of singular interest.

After 6 years, women on placebo had lost very little bone. The amount lost was statistically significant, but clinically inconsequential. The average BMD in women on placebo decreased 3% in the spine and 2% in the hip. Thus, the average rate of bone loss was about 0.5% per year.

A bone mass decrease of this extent represents a decline of about -0.3 T score, which is negligible. In the EPIC study, the 6-year fracture benefit, based on any type of fracture, boils down to lowering the risk from 1 in 11 on placebo to 1 in 9 on alendronate. These healthy women in their 50s had a very low risk of fracture, and taking a drug for 6 years had very little benefit for fracture reduction.

Women in their 50s typically have about 10% to 15% less bone mass than women of 25 to 30, when bone mass is at its peak. That 10% to 15% lower BMD translates to a T score of –1 to –1.2 , which is currently being labeled as osteopenic. Many patients and physicians have come to feel that osteopenia must always be treated with our newer drugs.

We are discovering that starting healthy women in their 50s on osteoporosis prevention drugs carries an extremely high cost per fracture avoided. During the 10 years since the startup of the EPIC study, support for early drug intervention in healthy women still in their 50s has dwindled. Now, expert groups, including the National Osteoporosis Foundation and the US Preventive Services Task Force, advise waiting until age 65 before starting osteoporosis risk evaluation or considering drug intervention in women who are otherwise healthy.

In my practice, I give healthy women in their 50s permission not to take drugs if their risk of fracture within the next 5 to 10 years is low. The picture is quite different in postmenopausal women in their 50s who do have high fracture risk, such as those who have already had a fracture, or who have very low bone density or high exposure to glucocorticoids.

EPIC data support the concept that the rate of bone loss is quite slow after a year or 2 has elapsed after menopause.

We need to avoid medicalizing these patients simply because we have drugs that reduce bone loss or because women in their 50s have less bone mass than 25-year-olds.

BIBLIOGRAPHY

Hosking D, Chilvers CE, Christiansen C, et al. Prevention of bone loss with alendronate in postmenopausal women under 60 years of age. Early Postmenopausal Intervention Cohort Study Group. N Engl J Med. 1998;338:485-492.

Wasnich RD, Bagger YZ, Hosking DJ, et al. Changes in bone density and turnover after alendronate or estrogen withdrawal. Menopause. 2004;11:622-630.

Siris ES, Bilezikian JP, Rubin MR, et al. Pins and plasters aren’t enough: a call for the evaluation and treatment of patients with osteoporotic fractures. J Clin Endocrinol Metab. 2003;88:3482-3486.

Rosen CJ, Black DM, Greenspan SL. Vignettes in osteoporosis: a road map to successful therapeutics. J Bone Miner Res. 2004;19:3-10.

HORMONE THERAPYDoes age affect mortality rate in postmenopausal women using HT?

Salpeter SR, Walsh JME, Greyber E, Ormiston TM, Salpeter EE. Mortality associated with hormone replacement therapy in younger and older women. J Gen Intern Med. 2004;19:791–804. META-ANALYSIS

This study attempted to discover whether the age of the postmenopausal woman using hormone therapy affects mortality. Investigators performed a meta-analysis of clinical trials that reported mortality rates associated with use of postmenopausal hormone therapy, and analyzed the results based on mean ages.

They reported a significant trend between increasing risk of mortality and increasing mean age of the women using hormone therapy—raising the possibility of a health benefit for younger postmenopausal women.

The studies included in the metaanalysis varied in entry criteria, outcomes assessed, number of subjects, and HT type and dosage. Furthermore, because age groups were defined by mean age in each trial rather than actual age of pooled participants, some overlap in ages likely occurred between the analyses of younger and older women.

In postmenopausal women younger than 60, the total mortality rate was reduced by 39% in women taking estrogen-containing hormone therapy, which was significant; in women older than 60, there was no significant effect on total mortality.

The data were from 30 randomized, controlled clinical trials published between 1966 and 2002, and included 26,708 women taking estrogen (ET) or estrogen plus progestogen (EPT). Data were pooled to determine total mortality and mortality due to specific causes such as cardiovascular disease and cancer. The mean trial duration was 4.5 years, and the mean age was 62.2 years.

When the study population was divided into younger and older age groups based on mean ages, it was found that those younger than 60 (mean age, 53.9) had a significantly reduced OR for total mortality of 0.61 (95% CI, 0.39–0.95) and those older than age 60 (mean age, 64.6) had an OR of 1.03 (95% CI, 0.90–1.18).

For specific causes, the OR for cardiovascular disease mortality associated with ET/EPT was 1.10 (95% CI, 0.90–1.34). For overall cancer mortality, the OR was 1.03 (95% CI, 0.82–1.29) and for breast cancer mortality, the OR was 1.03 (95% CI, 0.29–3.67).

For causes other than cardiovascular disease or cancer, mortality was significantly lower in women on HT: OR 0.67 (95% CI, 0.51–0.88). When divided into younger and older age groups, ET/EPT was not associated with a significant change in mortality, with the exception of reduced mortality from causes other than cardiovascular disease and cancer in the older age group (OR, 0.68; 95% CI, 0.56–0.91).

Does HT improve insulin resistance?

Margolis KL, Bonds DE, Rodabough RJ, et al, for the Women’s Health Initiative Investigators. Effect of oestrogen plus progestin on the incidence of diabetes in postmenopausal women: results from the Women’s Health Initiative Hormone Trial. Diabetologia. 2004;47:1175–1187. LEVEL 1 EVIDENCE: Randomized, controlled trial

Hormone therapy, compared with placebo, was associated with 15 fewer cases of diabetes per 10,000 women per year. Fasting glucose and insulin decreased compared with placebo, and may suggest improved insulin resistance. Although others have reported similar results, it is unlikely that hormone therapy will be prescribed to prevent diabetes, given its greater risk than benefit for other outcomes observed in other WHI analyses.

In the EPT part of WHI, a total of 15,641 postmenopausal women aged 50 to 79 were assigned to placebo or continuous-combined EPT (0.625 mg/day conjugated equine estrogens plus 2.5 mg/day medroxyprogesterone acetate). The incidence of diabetes was based on self-reports of insulin or oral diabetes drug treatment. Fasting glucose, insulin, and lipoproteins were measured at 1 and 3 years. After 5.6 years, the incidence of treated diabetes was 3.5% in the EPT group and 4.2% in the placebo group (hazard ratio, 0.79; 95% CI, 0.67–0.93; P= 0.004). Decreases in fasting glucose and insulin, suggesting decreased insulin resistance, were significant at 1 year in EPT users compared with placebo. The authors concluded that EPT reduces the incidence of diabetes possibly through a decrease in insulin resistance.

To be sure that a drug prevents a disease, everyone with the disease should be excluded at baseline, and at the end of the trial, everyone should be tested for the disease—if it is commonly undiagnosed. To study the incidence of new diabetes, all women (6%) with self-reported diabetes at baseline were excluded, and correctly so. But half of US adults with diabetes are undiagnosed. The WHI 6% prevalence is half of the assumed 12% prevalence in older overweight women. In the WHI, average age was 63 years and average body mass index was 28. Thus, it is not certain that the reduced risk occurred in women who were diabetes-free at baseline.

Fasting glucose was reduced in the EPT part of WHI, as in the Postmenopausal Estrogen Progestin Intervention (PEPI) trial. But 2-hour glucose levels were elevated by hormone treatment in PEPI, and were not measured in the WHI. Many studies have shown that postprandial or post-challenge glucose is a stronger risk factor for cardiovascular disease than fasting hyperglycemia.

Could an elevated post-challenge glucose have played a role in the unexpected excess cardiovascular disease observed with hormone therapy in healthy women in WHI and with hormone therapy in women with documented coronary heart disease in the Heart and Estrogen/progestin Replacement Study (HERS)?

Will transdermal estrogen reduce both fasting and post-challenge glucose? These and other questions remain. (EBC)

Lifestyle changes work best

• This report raises the possibility but does not justify prescribing EPT for diabetes prevention.

Postmenopausal women randomized to EPT had a lower incidence of treated diabetes, by self-report, than women assigned to placebo: a 21% relative risk reduction over 3 years. At 1 year, a comparison of changes from baseline in estimated insulin resistance (HOMA model) in a subgroup indicated a significant reduction with EPT compared with placebo group, but no significant difference at 3 years.

Because of the far-reaching morbidity and mortality due to Type 2 diabetes, particularly from cardiovascular disease, prevention would have major benefits, but the authors acknowledge that this report does not justify prescribing this therapy for this purpose, given hazards previously reported in the WHI.

Still, we can bear in mind other means of reducing risk for diabetes. In the Diabetes Prevention Program,¹metformin reduced type 2 diabetes risk by 31%, and a diet plus exercise program reduced it even more: by 58% over approximately 3 years of follow-up in high-risk persons. People at risk for diabetes should be counseled to make lifestyle changes that can reduce this risk far more, and more safely, than might EPT. (CGS)

Consider diabetes implications

• EPT can reduce the incidence of diabetes to the same degree as medications used for cardiovascular disease prevention.²

Growing evidence indicates that reducing insulin resistance in women can prevent onset of diabetes,³and that improving insulin resistance can slow the progression of atherosclerosis.⁴ Observational studies⁵—the Heart and Estrogen/progestin Replacement Study (HERS),⁶ and now the WHI—strongly indicate that EPT reduces the incidence of diabetes in postmenopausal women. Notably, HERS and WHI findings were with continuous-combined estrogen with progestin, the latter often viewed as antagonistic to the beneficial effects of estrogen on carbohydrate metabolism.) Diabetes is much more devastating in women, and more likely to strike. The risk (3,000 of 10,000) in postmenopausal women equals or exceeds that of postmenopausal breast cancer, coronary disease, or hip fracture.⁷The time has come to consider health and cost implications of long-term HT, especially in women with diabetes risk factors: age, obesity, high systolic BP, high nonfasting glucose, antihypertensive drug use, low HDL, or Hispanic or African-American ethnicity. Clinical trials confirming HT’s benefit add to the totality of evidence that the benefits outweigh the risks.⁸Since long-term effects (>10 years) reflect only observational data, we urgently need studies designed to understand long-term benefits and risks. (HNH)

1. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346:393-403.

2. Pepine CJ, Cooper-Dehoff RM. Cardiovascular therapies and risk for development of diabetes. J Am Coll Cardiol. 2004;44:509-512.

3. Buchanan TA, Xiang AH, Peters RK, et al. Preservation of pancreatic beta-cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance inhigh risk Hispanic women. Diabetes. 2002;51:2796-2803.

4. Xiang AH, Peters RK, Kjos SL, et al. Effect of thiazolidinedione treatment on progression of subclinical atherosclerosis in premenopausal women at high risk for type 2 diabetes. J Clin Endocrinol Metab. 2005;90:1986-1991.

5. Manson JE, Rimm EB, Colditz GA, et al. A prospective study of postmenopausal estrogen therapy and subsequent incidence of non-insulin-dependent diabetes mellitus. Ann Epidemiol. 1992;2:665-673.

6. Kanaya AM, Herrington D, et al. Glycemic effects of postmenopausal hormone therapy: Heart and Estrogen/progestin Replacement Study. Randomized, double-blind, placebo-controlled trial. Ann Intern Med. 2003;138:1-9.

7. Narayan KMV, Boyle JP, et al. Lifetime risk for diabetes mellitus in the US. JAMA 2003;290:1884-1890.

8. Philips LS, Langer RD. Postmenopausal hormone therapy: critical reappraisal and a unified hypothesis. Fertil Steril. 2005;83:558-566.

Soy versus placebo: Underwhelming

Red clover, likewise

Trebs EE, Ensrud KE, MacDonald R, Wilt TJ. Phytoestrogens for treatment of menopausal symptoms: a systematic review. Obstet Gynecol. 2004;104:824–836. META-ANALYSIS

Data on 2,348 women (mean age, 53.1 years) experiencing a mean of 7.1 hot flashes per week were analyzed. Only randomized controlled trials reporting menopausal symptoms of hot flashes, night sweats, and vaginal dryness were included. Mean trial duration was 17 weeks.

• The 11 soy food or beverage supplementtrials (N = 995 women) found no improvement compared with placebo.
• Of the 8 soy food trialsreporting hot flash outcomes, only 1 showed a significant improvement compared with placebo.
• In the 9 soy extract trials, overall results (N = 854) were mixed. In 5 trials using soy extracts and reporting hot flash frequency, 3 found no significant difference in symptoms between the soy and placebo groups; the other 2 (total 114 subjects) found significant improvements.
• The 5 red clover trials(N = 400) showed no improvement over placebo.

Many women in these studies appear to have been perimenopausal rather than postmenopausal. Nine studies included women who had had a menstrual period within the previous 3 to 6 months (late perimenopausal). A subgroup analysis of perimenopausal women would have been useful, since their endocrinologic status is quite different from that of postmenopausal women.

Does soy improve cognition, bone density, or lipids?

Kreijkamp-Kaspers S, Kok L, Grobbee DE, et al. Effect of soy protein containing isoflavones on cognitive function, bone mineral density, and plasma lipids in postmenopausal women: a randomized controlled trial. JAMA. 2004;292:65–74. LEVEL 1 EVIDENCE: Randomized, controlled trial

This careful trial raises the question of how to reconcile these results with animal and observational studies. In all, 202 postmenopausal women aged 60 to 75 years received 25.6 g/day of a soy protein supplement containing 99 mg isoflavones or a milk protein powder for 1 year. Adherence was monitored by serum genistein. There were no notable differences in:

• Memory, verbal skills, or concentration.
• Bone mineral density or bone-specific alkaline phosphatase, calcium, or phosphorus levels.
• Cholesterol, triglycerides, and lipoprotein plasma levels. These findings may not relate to perimenopausal women, in whom soy has been seen to significantly reduce LDL, but only during midfollicular and periovulatory phases.¹ Premenopausal² but not postmenopausal³monkeys given soy have had beneficial effects on bone quality.

REFERENCES

1. Merz-Demlow BE, Duncan AM, Wangen KE, et al. Soy isoflavones improve plasma lipids in normocholes-terolemic, premenopausal women. Am J Clin Nutr. 2000;71:1462-1469.

2. Kaplan JR, et al. Supplementation reduces the trajectory of atherogenesis in premenopausal monkeys at high risk for development of extensive postmenopausal coronary artery plaques. Menopause. 2004;11:653. Abstract S-17.

3. Register TC, Jayo MJ, Anthony MS. Soy phytoestrogens do not prevent bone loss in postmenopausal monkeys. J Clin Endocrinol Metab. 2003;88:4362-4370.

LIFESTYLE THERAPYThe secret to keeping those girlish carotids

Wildman RP, Schott LL, Brockwell S, Kuller LH, Sutton-Tyrrell K. A dietary and exercise intervention slows menopause-associated progression of subclinical atherosclerosis as measured by intima-media thickness of the carotid arteries. J Am Coll Cardiol. 2004;44:579–585. LEVEL 1 EVIDENCE: Randomized, controlled trial

These important findings are strong evidence that diet and exercise can slow the subclinical atherosclerosis progression that accompanies the menopause transition.

The Women’s Healthy Lifestyle Project previously found that weight gain and increased lipids, glucose, and blood pressure often accompany the menopause transition.¹ This report describes improvements with diet and exercise intervention, compared with controls.

A total of 535 women aged 44 to 50 years were randomized to lifestyle intervention or assessment-only. All were premenopausal, and all had normal to high-normal body mass index, diastolic blood pressure, and fasting glucose and cholesterol levels.

The diet and exercise regimen used in the study was designed to reduce fat and cholesterol, prevent weight gain, and increase physical activity.

End points were progression of intimamedia thickness in the common carotid artery, internal carotid artery, and bulb segments.

The control group had significantly greater increases in intima-media thickness in women who became postmenopausal compared with those who remained premenopausal.

For women who became perimenopausal or postmenopausal during this 4-year study, diet and exercise slowed the progression of intima-media thickness by a 47% average reduction (P< 0.05), but had no effect on carotid segments in the women who remained premenopausal.

No benefit in intima media thickness was seen in women who remained premenopausal during the trial. Nevertheless, there are many well-documented benefits of healthy diet and exercise in premenopausal women.

Also of note, hormone therapy initiated after baseline measurements did not alter the results.

The message for patients, especially perimenopausal patients is that there is no time like the present to start a healthy lifestyle.

No downside

We’ve learned from the Nurse’s Health Study,²an observational study, that women who eat a healthy diet, do not smoke, and who exercise can reduce their risk of coronary heart disease by 57%.

We learned from the randomized controlled trial by the Diabetes Prevention Program Research Group³ that diet and exercise in high-risk women for 3 years can reduce incidence of new diabetes by 58%.

Now, in this trial, we learn that diet and exercise can reduce the progression of atherosclerosis in perimenopausal women by nearly 50%.

Since there is little, if any, downside to healthy living, why wait?

Dr. Utian has served as an advisor/consultant for Eli Lilly, Pfizer, and Novartis. He has received research funding from Amylin, 3m, Barr, Berlex, BMS, Eli Lilly, Forest, Galen, Glaxo Smith Kline, Neurocrine Biosciences, Novartis, Novo Nordisk, Organon, Pharmacia, P&G, Pfizer, Roche, Sepracor, Solvay, Wyeth, and Yamanouchi.

Dr. Ettinger has served as an advisor for Berlex, Duramed-Barr, Glaxo Smith Kline, and P&G.

REFERENCES

1. Kuller LH, Simkin-Silverman LR, Wing RR, Meilahn EN, Ives DG. Women’s Healthy Lifestyle Project: a randomized clinical trial: results at 54 months. Circulation. 2001;103:32-37.

2. Stampfer MJ, Hu FB, Manson JE, Rimm EB, Willett WC. Primary prevention of coronary heart disease in women through diet and lifestyle. N Engl J Med. 2000;343:16-22.

3. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346:393-403.

An eclamptic convulsion is frightening to behold. First, the woman’s face becomes distorted, and her eyes protrude. Then her face acquires a congested expression, and foam may exude from her mouth. Breathing stops.

Because eclampsia is so frightening, the natural tendency is to try to stop a convulsion, but this is not the wisest strategy.

Rather, the foremost priorities are to avoid maternal injury and support cardiovascular functions. How to do this, and how to prevent further convulsions, monitor and deliver the fetus, and avert complications are the focus of this article.

Since eclampsia may be fatal for both mother and fetus, all labor and delivery units and all obstetricians should be prepared to diagnose and manage this grave threat. However, few obstetric units encounter more than 1 or 2 cases a year; most obstetricians have little or no experience managing acute eclampsia. In the Western world, it affects only 1 in 2,000 to 1 in 3,448 pregnancies.^1-4

How a convulsion happens

Most convulsions occur in 2 phases and last for 60 to 75 seconds. The first phase, lasting 15 to 20 seconds, begins with facial twitching, soon followed by a rigid body with generalized muscular contractions.

In the second phase, which lasts about a minute, the muscles of the body alternately contract and relax in rapid succession. This phase begins with the muscles of the jaw and rapidly encompasses eyelids, other facial muscles, and body. If the tongue is unprotected, the woman often bites it.

Coma sometimes follows the convulsion, and deep, rapid breathing usually begins as soon as the convulsion stops. In fact, maintaining oxygenation typically is not a problem after a single convulsion, and the risk of aspiration is low in a well managed patient.

Upon reviving, the woman typically remembers nothing about the seizure.

If convulsions recur, some degree of consciousness returns after each one, although the woman may become combative, agitated, and difficult to control.

Harbingers of complications

In the developed world, eclampsia increases the risk of maternal death (range: 0 to 1.8%).^1-5 A recent review of all reported pregnancy-related deaths in the United States from 1979 to 1992 found 4,024 cases.⁶ Of these, 790 (19.6%) were due to preeclampsia-eclampsia, 49% of which were caused by eclampsia. The risk of death from preeclampsia or eclampsia was higher for the following groups:

• women over 30,
• no prenatal care,
• African Americans, and
• onset of preeclampsia or eclampsia before 28 weeks.⁶

Maternal morbidity

Pregnancies complicated by eclampsia also have higher rates of maternal morbidity such as pulmonary edema and HELLP syndrome (TABLE 1). Complications are substantially higher among women who develop antepartum eclampsia, especially when it is remote from term.^1-3

TABLE 1

Maternal complications

Antepartum eclampsia, especially when it is remote from term, is much more likely to lead to complications

Adverse perinatal outcomes

Perinatal mortality and morbidity are high in eclampsia, with a perinatal death rate in recent series of 5.6% to 11.8%.^1,7 This high rate is related to prematurity, abruptio placentae, and severe growth restriction.¹

Preterm deliveries occur in approximately 50% of cases, and about 25% occur before 32 weeks’ gestation.¹

Diagnosis can be tricky

When the patient has generalized edema, hypertension, proteinuria, and convulsions, diagnosis of eclampsia is straightforward. Unfortunately, women with eclampsia exhibit a broad spectrum of signs, ranging from severe hypertension, severe proteinuria, and generalized edema, to absent or minimal hypertension, nonexistent proteinuria, and no edema (TABLE 2).¹

Hypertension is the hallmark of diagnosis. Hypertension is severe (at least 160 mm Hg systolic and/or at least 110 mm Hg diastolic) in 20% to 54% of cases, and it is mild (systolic pressure between 140 and 160 mm Hg or diastolic pressure between 90 and 110 mm Hg) in 30% to 60% of cases.^2,3 In 16% of cases, there may be no hypertension at all.²

Proteinuria. Eclampsia usually is associated with proteinuria (at least 1+ on dipstick).¹ However, when I studied a series of 399 women with eclampsia, I found substantial proteinuria (3+ or above on dipstick) in only 48% of cases; proteinuria was absent in 14%.²

Edema. A weight gain of more than 2 lb per week (with or without clinical edema) during the third trimester may be the first sign of eclampsia. However, in my series of 399 women, edema was absent in 26% of cases.²

TABLE 2

Signs and symptoms of eclampsia*

Hypertension and proteinuria in eclampsia may be severe, mild, or even absent

Symptoms of eclampsia

Several clinical symptoms can occur before or after a convulsion¹:

• persistent occipital or frontal headaches,
• blurred vision,
• photophobia,
• epigastric and/or right upper quadrant pain, and
• altered mental status.

Usual times of onset

Eclamptic convulsions can occur during pregnancy or delivery, or after delivery ( TABLE 3).^1-5

Approximately 91% of antepartum cases develop at 28 weeks or beyond. The remaining cases tend to occur between 21 and 27 weeks’ gestation (7.5%), or at or before 20 weeks (1.5%).²

When eclampsia occurs before 20 weeks, it usually involves molar or hydropic degeneration of the placenta, with or without a fetus.¹ However, eclampsia can occur in the first half of pregnancy without molar degeneration of the placenta, although this is rare.^1,2 These women are sometimes misdiagnosed as having hypertensive encephalopathy, seizure disorder, or thrombotic thrombocytopenia purpura. Thus, women who develop convulsions in association with hypertension and proteinuria in the first half of pregnancy should be assumed to have eclampsia until proven otherwise,¹ and require ultrasound examination of the uterus to rule out molar pregnancy and/or hydropic or cystic degeneration of the placenta.

Postpartum cases tend to occur within the first 48 hours, although some develop beyond this limit and have been reported as late as 23 days postpartum.⁸

Late postpartum eclampsia occurs more than 48 hours but less than 4 weeks after delivery.⁸ These women have signs and symptoms consistent with preeclampsia along with their convulsions.^8,9 Thus, women who develop convulsions with hypertension and/or proteinuria, or with headaches or blurred vision, after 48 hours postpartum should be assumed to have eclampsia and treated accordingly.^8,9

When eclampsia occurs especially late, perform an extensive neurologic examination to rule out other cerebral pathology.^1,10

Eclampsia is atypical if convulsions occur before 20 weeks’ gestation or beyond 48 hours postpartum. It also is atypical if convulsions develop or persist despite adequate magnesium sulfate, or if the patient develops focal neurologic deficits, disorientation, blindness, or coma. In these cases, conduct a neurologic exam and cerebral imaging to exclude neurologic pathology.^8-10

TABLE 3

Usual times of onset*

91% of antepartum eclampsia cases occur at 28 weeks or later, although eclamptic convulsions can occur at any time during pregnancy or delivery, or postpartum

Differential diagnosis

As with other aspects of preeclampsia, the presenting symptoms, clinical findings, and many laboratory results in eclampsia overlap several other medical and surgical conditions.^1,10 Of course, eclampsia is the most common cause of convulsions in a woman with hypertension and/or proteinuria during pregnancy or immediately postpartum. On rare occasions, other causes of convulsions in pregnancy or postpartum may mimic eclampsia.¹ These potential diagnoses are particularly important when the woman has focal neurologic deficits, prolonged coma, or atypical eclampsia.

The differential diagnosis encompasses a variety of cerebrovascular and metabolic disorders:

• hemorrhage,
• ruptured aneurysm or malformation,
• arterial embolism, thrombosis,
• venous thrombosis,
• hypoxic ischemic encephalopathy,
• angiomas,
• hypertensive encephalopathy,
• seizure disorder,
• hypoglycemia, hyponatremia,
• posterior leukoencephalopathy syndrome,
• thrombotic thrombocytopenic purpura,
• postdural puncture syndrome, and
• cerebral vasculitis/angiopathy.

Other diseases may factor in

Some women develop gestational hypertension or preeclampsia in association with connective tissue disease, thrombophilias, seizure disorder, or hypertensive encephalopathy, further confounding the diagnosis.

Thus, make every effort to ensure a correct diagnosis, since management may differ among these conditions.

Managing convulsions

Do not try to stop the first convulsion

The natural tendency is to try and interrupt the convulsion, but this is not recommended. Nor should you give a drug such as diazepam to shorten or stop the convulsion, especially if the patient lacks an intravenous line and no one skilled in intubation is immediately available. If diazepam is given, do not exceed 5 mg over 60 seconds. Rapid administration of this drug may lead to apnea or cardiac arrest, or both.

Steps to prevent maternal injury

During or immediately after the acute convulsive episode, take steps to prevent serious maternal injury and aspiration, assess and establish airway patency, and ensure maternal oxygenation (TABLE 4).

Elevate and pad the bed’s side rails and insert a padded tongue blade between the patient’s teeth, taking care not to trigger the gag reflex.

Physical restraints also may be needed.

Prevent aspiration. To minimize the risk of aspiration, place the patient in the lateral decubitus position, and suction vomitus and oral secretions as needed. Be aware that aspiration can occur when the padded tongue blade is forced to the back of the throat, stimulating the gag reflex and resultant vomiting.

TABLE 4

During a convulsion, 3 spheres of concern

Tips on supplemental oxygenation

Although the initial seizure lasts only a minute or 2, it is important to maintain oxygenation by giving supplemental oxygen via a face mask, with or without an oxygen reservoir, at 8 to 10 L per minute. This is important because hypoventilation and respiratory acidosis often occur.

Once the convulsion ends and the patient resumes breathing, oxygenation is rarely a problem. However, maternal hypoxemia and acidosis can develop in women with repetitive convulsions, aspiration pneumonia, pulmonary edema, or a combination of these factors. Thus, transcutaneous pulse oximetry is advisable to monitor oxygenation in eclamptic patients.

Arterial blood gas analysis is necessary if pulse oximetry shows abnormal oxygen saturation (ie, at or below 92%).

Strategy to prevent recurrence

Magnesium sulfate is the drug of choice to treat and prevent subsequent convulsions in women with eclampsia.^1,2

Dosage. I give a loading dose of 6 g over 15 to 20 minutes, followed by a maintenance dose of 2 g per hour as a continuous intravenous solution.

Approximately 10% of eclamptic women have a second convulsion after receiving magnesium sulfate.^1,2 When this occurs, I give another 2-g bolus intravenously over 3 to 5 minutes.

More rarely, a woman will continue to have convulsions while receiving adequate and therapeutic doses of magnesium sulfate.

I treat such patients with sodium amobarbital, 250 mg, intravenously over 3 to 5 minutes.

Monitor maternal magnesium levels

Plasma levels should be in the range of 4 to 8 mg/dL during treatment for eclampsia, and are determined by the volume of distribution and by renal excretion. Thus, it is important to monitor the patient for magnesium toxicity, particularly if she has renal dysfunction (serum creatinine of 1.2 mg/dL or above) or urine output below 100 mL in 4 hours. In these women, adjust the maintenance dose according to plasma levels.

Side effects of magnesium including flushing, a feeling of warmth, nausea and vomiting, double vision, and slurred speech (TABLE 5).

If magnesium toxicity is suspected, immediately discontinue the infusion and administer supplemental oxygen along with 10 mL of 10% calcium gluconate (1 g total) as an intravenous push slowly over 5 minutes.

If respiratory arrest occurs, prompt resuscitation—including intubation and assisted ventilation—is vital.

TABLE 5

Clinical manifestations of magnesium toxicity

Maternal plasma levels of 4 to 8 mg/dL are appropriate during treatment for eclampsia; higher levels signal toxicity

Controlling severe hypertension

The next step is to reduce blood pressure to a safe range. The objective: to preserve cerebral autoregulation and prevent congestive heart failure without compromising cerebral perfusion or jeopardizing uteroplacental blood flow, which is already reduced in many women with eclampsia.¹

To these ends, try to keep systolic blood pressure between 140 and 160 mm Hg and diastolic pressure between 90 and 110 mm Hg. This can be achieved with:

• bolus 5- to 10-mg doses of hydralazine,
• 20 to 40 mg labetalol intravenously every 15 minutes, as needed, or
• 10 to 20 mg oral nifedipine every 30 minutes.

Other potent antihypertensive drugs such as sodium nitroprusside or nitroglycerine are rarely needed in eclampsia, and diuretics are indicated only in the presence of pulmonary edema.

Intrapartum management

Maternal hypoxemia and hypercarbia cause fetal heart rate and uterine activity changes during and immediately following a convulsion.

Fetal heart rate changes

These can include bradycardia, transient late decelerations, decreased beat-to-beat variability, and compensatory tachycardia.

The interval from onset of the seizure to the fall in fetal heart rate is approximately 5 minutes (FIGURE 1). Transitory fetal tachycardia frequently occurs after the prolonged bradycardia. The loss of beat-to-beat variability, with transitory late decelerations, occurs during the recovery phase.

The mechanism for the transient fetal bradycardia may be intense vasospasm and uterine hyperactivity, which may decrease uterine blood flow. The absence of maternal respiration during the convulsion may also contribute to fetal heart rate changes.

Since the fetal heart rate usually returns to normal after a convulsion, other conditions should be considered if an abnormal pattern persists.

In some cases, it may take longer for the heart rate pattern to return to baseline if the fetus is preterm with growth restriction.

Placental abruption may occur after the convulsion and should be suspected if fetal bradycardia or repetitive late decelerations persist (FIGURE 2).

FIGURE 1 Fetal response to a convulsion The top 2 tracings show fetal bradycardia during an eclamptic convulsion

FIGURE 2 Abruptio placentae Repetitive late decelerations secondary to abruptio placentae, necessitating cesarean section

Uterine activity

During a convulsion, contractions can increase in frequency and tone. The duration of increased uterine activity varies from 2 to 14 minutes.

These changes usually resolve spontaneously within 3 to 10 minutes following the termination of convulsions and correction of maternal hypoxemia (FIGURE 1).

If uterine hyperactivity persists, suspect placental abruption (FIGURE 2).

Do not rush to cesarean

It benefits the fetus to allow in utero recovery from the maternal convulsion, hypoxia, and hypercarbia before delivery. However, if the bradycardia and/or recurrent late decelerations persist beyond 10 to 15 minutes despite all efforts, suspect abruptio placentae or nonreassuring fetal status.

Once the patient regains consciousness and is oriented to name, place, and time, and her convulsions are controlled and condition stabilized, proceed with delivery.

Choosing a delivery route

Eclampsia is not an indication for cesarean. The decision to perform a cesarean should be based on fetal gestational age, fetal condition, presence of labor, and cervical Bishop score. I recommend:

• Cesarean section for women with eclampsia before 30 weeks’ gestation who are not in labor and whose Bishop score is below 5.
• Vaginal delivery for women in labor or with rupture of membranes, provided there are no obstetric complications.
• Labor induction with oxytocin infusion or prostaglandins in all women at or after 30 weeks, regardless of the Bishop score, and in women before 30 weeks when the Bishop score is 5 or above.

Maternal pain relief

During labor and delivery, systemic opioids or epidural anesthesia can provide pain relief—the same recommendations as for women with severe preeclampsia.

For cesarean delivery, an epidural, spinal, or combined techniques of regional anesthesia are suitable.

Do not use regional anesthesia if there is coagulopathy or severe thrombocytopenia (platelet count less than 50,000/mm³). In women with eclampsia, general anesthesia increases the risk of aspiration and failed intubation due to airway edema, and is associated with marked increases in systemic and cerebral pressures during intubation and extubation.

Women with airway or laryngeal edema may require awake intubation under fiber optic observation, with tracheostomy immediately available.

Changes in systemic or cerebral pressures may be attenuated by pretreatment with labetalol or nitroglycerine injections.

Postpartum management

After delivery, women with eclampsia require close monitoring of vital signs, fluid intake and output, and symptoms for at least 48 hours.

Risk of pulmonary edema

These women usually receive large amounts of intravenous fluids during labor, delivery, and postpartum. In addition, during the postpartum period, extracellular fluid mobilizes, leading to increased intravascular volume.

As a result, women who develop eclampsia—particularly those with abnormal renal function, abruptio placentae, and/or preexisting chronic hypertension— face an increased risk for pulmonary edema and exacerbation of severe hypertension.²

Frequent evaluation of the amount of intravenous fluids is necessary, as well as oral intake, blood products, and urine output. They also need pulse oximetry and pulmonary auscultation.

Continue magnesium sulfate

Parenteral magnesium sulfate should be given for at least 24 hours after delivery and/or for at least 24 hours after the last convulsion.

If the patient has oliguria (less than 100 mL over 4 hours), both fluid administration and the dose of magnesium sulfate should be reduced.

Oral antihypertensives

Other oral antihypertensive agents such as labetalol or nifedipine can be given to keep systolic blood pressure below 155 mm Hg and diastolic blood pressure below 105 mm Hg. Nifedipine offers the benefit of improved diuresis in the postpartum period.

The author reports no financial relationships relevant to this article.

An eclamptic convulsion is frightening to behold. First, the woman’s face becomes distorted, and her eyes protrude. Then her face acquires a congested expression, and foam may exude from her mouth. Breathing stops.

Because eclampsia is so frightening, the natural tendency is to try to stop a convulsion, but this is not the wisest strategy.

Rather, the foremost priorities are to avoid maternal injury and support cardiovascular functions. How to do this, and how to prevent further convulsions, monitor and deliver the fetus, and avert complications are the focus of this article.

Since eclampsia may be fatal for both mother and fetus, all labor and delivery units and all obstetricians should be prepared to diagnose and manage this grave threat. However, few obstetric units encounter more than 1 or 2 cases a year; most obstetricians have little or no experience managing acute eclampsia. In the Western world, it affects only 1 in 2,000 to 1 in 3,448 pregnancies.^1-4

How a convulsion happens

Most convulsions occur in 2 phases and last for 60 to 75 seconds. The first phase, lasting 15 to 20 seconds, begins with facial twitching, soon followed by a rigid body with generalized muscular contractions.

In the second phase, which lasts about a minute, the muscles of the body alternately contract and relax in rapid succession. This phase begins with the muscles of the jaw and rapidly encompasses eyelids, other facial muscles, and body. If the tongue is unprotected, the woman often bites it.

Coma sometimes follows the convulsion, and deep, rapid breathing usually begins as soon as the convulsion stops. In fact, maintaining oxygenation typically is not a problem after a single convulsion, and the risk of aspiration is low in a well managed patient.

Upon reviving, the woman typically remembers nothing about the seizure.

If convulsions recur, some degree of consciousness returns after each one, although the woman may become combative, agitated, and difficult to control.

Harbingers of complications

In the developed world, eclampsia increases the risk of maternal death (range: 0 to 1.8%).^1-5 A recent review of all reported pregnancy-related deaths in the United States from 1979 to 1992 found 4,024 cases.⁶ Of these, 790 (19.6%) were due to preeclampsia-eclampsia, 49% of which were caused by eclampsia. The risk of death from preeclampsia or eclampsia was higher for the following groups:

• women over 30,
• no prenatal care,
• African Americans, and
• onset of preeclampsia or eclampsia before 28 weeks.⁶

Maternal morbidity

Pregnancies complicated by eclampsia also have higher rates of maternal morbidity such as pulmonary edema and HELLP syndrome (TABLE 1). Complications are substantially higher among women who develop antepartum eclampsia, especially when it is remote from term.^1-3

TABLE 1

Maternal complications

Antepartum eclampsia, especially when it is remote from term, is much more likely to lead to complications

Adverse perinatal outcomes

Perinatal mortality and morbidity are high in eclampsia, with a perinatal death rate in recent series of 5.6% to 11.8%.^1,7 This high rate is related to prematurity, abruptio placentae, and severe growth restriction.¹

Preterm deliveries occur in approximately 50% of cases, and about 25% occur before 32 weeks’ gestation.¹

Diagnosis can be tricky

When the patient has generalized edema, hypertension, proteinuria, and convulsions, diagnosis of eclampsia is straightforward. Unfortunately, women with eclampsia exhibit a broad spectrum of signs, ranging from severe hypertension, severe proteinuria, and generalized edema, to absent or minimal hypertension, nonexistent proteinuria, and no edema (TABLE 2).¹

Hypertension is the hallmark of diagnosis. Hypertension is severe (at least 160 mm Hg systolic and/or at least 110 mm Hg diastolic) in 20% to 54% of cases, and it is mild (systolic pressure between 140 and 160 mm Hg or diastolic pressure between 90 and 110 mm Hg) in 30% to 60% of cases.^2,3 In 16% of cases, there may be no hypertension at all.²

Proteinuria. Eclampsia usually is associated with proteinuria (at least 1+ on dipstick).¹ However, when I studied a series of 399 women with eclampsia, I found substantial proteinuria (3+ or above on dipstick) in only 48% of cases; proteinuria was absent in 14%.²

Edema. A weight gain of more than 2 lb per week (with or without clinical edema) during the third trimester may be the first sign of eclampsia. However, in my series of 399 women, edema was absent in 26% of cases.²

TABLE 2

Signs and symptoms of eclampsia*

Hypertension and proteinuria in eclampsia may be severe, mild, or even absent

Symptoms of eclampsia

Several clinical symptoms can occur before or after a convulsion¹:

• persistent occipital or frontal headaches,
• blurred vision,
• photophobia,
• epigastric and/or right upper quadrant pain, and
• altered mental status.

Usual times of onset

Eclamptic convulsions can occur during pregnancy or delivery, or after delivery ( TABLE 3).^1-5

Approximately 91% of antepartum cases develop at 28 weeks or beyond. The remaining cases tend to occur between 21 and 27 weeks’ gestation (7.5%), or at or before 20 weeks (1.5%).²

When eclampsia occurs before 20 weeks, it usually involves molar or hydropic degeneration of the placenta, with or without a fetus.¹ However, eclampsia can occur in the first half of pregnancy without molar degeneration of the placenta, although this is rare.^1,2 These women are sometimes misdiagnosed as having hypertensive encephalopathy, seizure disorder, or thrombotic thrombocytopenia purpura. Thus, women who develop convulsions in association with hypertension and proteinuria in the first half of pregnancy should be assumed to have eclampsia until proven otherwise,¹ and require ultrasound examination of the uterus to rule out molar pregnancy and/or hydropic or cystic degeneration of the placenta.

Postpartum cases tend to occur within the first 48 hours, although some develop beyond this limit and have been reported as late as 23 days postpartum.⁸

Late postpartum eclampsia occurs more than 48 hours but less than 4 weeks after delivery.⁸ These women have signs and symptoms consistent with preeclampsia along with their convulsions.^8,9 Thus, women who develop convulsions with hypertension and/or proteinuria, or with headaches or blurred vision, after 48 hours postpartum should be assumed to have eclampsia and treated accordingly.^8,9

When eclampsia occurs especially late, perform an extensive neurologic examination to rule out other cerebral pathology.^1,10

Eclampsia is atypical if convulsions occur before 20 weeks’ gestation or beyond 48 hours postpartum. It also is atypical if convulsions develop or persist despite adequate magnesium sulfate, or if the patient develops focal neurologic deficits, disorientation, blindness, or coma. In these cases, conduct a neurologic exam and cerebral imaging to exclude neurologic pathology.^8-10

TABLE 3

Usual times of onset*

91% of antepartum eclampsia cases occur at 28 weeks or later, although eclamptic convulsions can occur at any time during pregnancy or delivery, or postpartum

Differential diagnosis

As with other aspects of preeclampsia, the presenting symptoms, clinical findings, and many laboratory results in eclampsia overlap several other medical and surgical conditions.^1,10 Of course, eclampsia is the most common cause of convulsions in a woman with hypertension and/or proteinuria during pregnancy or immediately postpartum. On rare occasions, other causes of convulsions in pregnancy or postpartum may mimic eclampsia.¹ These potential diagnoses are particularly important when the woman has focal neurologic deficits, prolonged coma, or atypical eclampsia.

The differential diagnosis encompasses a variety of cerebrovascular and metabolic disorders:

• hemorrhage,
• ruptured aneurysm or malformation,
• arterial embolism, thrombosis,
• venous thrombosis,
• hypoxic ischemic encephalopathy,
• angiomas,
• hypertensive encephalopathy,
• seizure disorder,
• hypoglycemia, hyponatremia,
• posterior leukoencephalopathy syndrome,
• thrombotic thrombocytopenic purpura,
• postdural puncture syndrome, and
• cerebral vasculitis/angiopathy.

Other diseases may factor in

Some women develop gestational hypertension or preeclampsia in association with connective tissue disease, thrombophilias, seizure disorder, or hypertensive encephalopathy, further confounding the diagnosis.

Thus, make every effort to ensure a correct diagnosis, since management may differ among these conditions.

Managing convulsions

Do not try to stop the first convulsion

The natural tendency is to try and interrupt the convulsion, but this is not recommended. Nor should you give a drug such as diazepam to shorten or stop the convulsion, especially if the patient lacks an intravenous line and no one skilled in intubation is immediately available. If diazepam is given, do not exceed 5 mg over 60 seconds. Rapid administration of this drug may lead to apnea or cardiac arrest, or both.

Steps to prevent maternal injury

During or immediately after the acute convulsive episode, take steps to prevent serious maternal injury and aspiration, assess and establish airway patency, and ensure maternal oxygenation (TABLE 4).

Elevate and pad the bed’s side rails and insert a padded tongue blade between the patient’s teeth, taking care not to trigger the gag reflex.

Physical restraints also may be needed.

Prevent aspiration. To minimize the risk of aspiration, place the patient in the lateral decubitus position, and suction vomitus and oral secretions as needed. Be aware that aspiration can occur when the padded tongue blade is forced to the back of the throat, stimulating the gag reflex and resultant vomiting.

TABLE 4

During a convulsion, 3 spheres of concern

Tips on supplemental oxygenation

Although the initial seizure lasts only a minute or 2, it is important to maintain oxygenation by giving supplemental oxygen via a face mask, with or without an oxygen reservoir, at 8 to 10 L per minute. This is important because hypoventilation and respiratory acidosis often occur.

Once the convulsion ends and the patient resumes breathing, oxygenation is rarely a problem. However, maternal hypoxemia and acidosis can develop in women with repetitive convulsions, aspiration pneumonia, pulmonary edema, or a combination of these factors. Thus, transcutaneous pulse oximetry is advisable to monitor oxygenation in eclamptic patients.

Arterial blood gas analysis is necessary if pulse oximetry shows abnormal oxygen saturation (ie, at or below 92%).

Strategy to prevent recurrence

Magnesium sulfate is the drug of choice to treat and prevent subsequent convulsions in women with eclampsia.^1,2

Dosage. I give a loading dose of 6 g over 15 to 20 minutes, followed by a maintenance dose of 2 g per hour as a continuous intravenous solution.

Approximately 10% of eclamptic women have a second convulsion after receiving magnesium sulfate.^1,2 When this occurs, I give another 2-g bolus intravenously over 3 to 5 minutes.

More rarely, a woman will continue to have convulsions while receiving adequate and therapeutic doses of magnesium sulfate.

I treat such patients with sodium amobarbital, 250 mg, intravenously over 3 to 5 minutes.

Monitor maternal magnesium levels

Plasma levels should be in the range of 4 to 8 mg/dL during treatment for eclampsia, and are determined by the volume of distribution and by renal excretion. Thus, it is important to monitor the patient for magnesium toxicity, particularly if she has renal dysfunction (serum creatinine of 1.2 mg/dL or above) or urine output below 100 mL in 4 hours. In these women, adjust the maintenance dose according to plasma levels.

Side effects of magnesium including flushing, a feeling of warmth, nausea and vomiting, double vision, and slurred speech (TABLE 5).

If magnesium toxicity is suspected, immediately discontinue the infusion and administer supplemental oxygen along with 10 mL of 10% calcium gluconate (1 g total) as an intravenous push slowly over 5 minutes.

If respiratory arrest occurs, prompt resuscitation—including intubation and assisted ventilation—is vital.

TABLE 5

Clinical manifestations of magnesium toxicity

Maternal plasma levels of 4 to 8 mg/dL are appropriate during treatment for eclampsia; higher levels signal toxicity

Controlling severe hypertension

The next step is to reduce blood pressure to a safe range. The objective: to preserve cerebral autoregulation and prevent congestive heart failure without compromising cerebral perfusion or jeopardizing uteroplacental blood flow, which is already reduced in many women with eclampsia.¹

To these ends, try to keep systolic blood pressure between 140 and 160 mm Hg and diastolic pressure between 90 and 110 mm Hg. This can be achieved with:

• bolus 5- to 10-mg doses of hydralazine,
• 20 to 40 mg labetalol intravenously every 15 minutes, as needed, or
• 10 to 20 mg oral nifedipine every 30 minutes.

Other potent antihypertensive drugs such as sodium nitroprusside or nitroglycerine are rarely needed in eclampsia, and diuretics are indicated only in the presence of pulmonary edema.

Intrapartum management

Maternal hypoxemia and hypercarbia cause fetal heart rate and uterine activity changes during and immediately following a convulsion.

Fetal heart rate changes

These can include bradycardia, transient late decelerations, decreased beat-to-beat variability, and compensatory tachycardia.

The interval from onset of the seizure to the fall in fetal heart rate is approximately 5 minutes (FIGURE 1). Transitory fetal tachycardia frequently occurs after the prolonged bradycardia. The loss of beat-to-beat variability, with transitory late decelerations, occurs during the recovery phase.

The mechanism for the transient fetal bradycardia may be intense vasospasm and uterine hyperactivity, which may decrease uterine blood flow. The absence of maternal respiration during the convulsion may also contribute to fetal heart rate changes.

Since the fetal heart rate usually returns to normal after a convulsion, other conditions should be considered if an abnormal pattern persists.

In some cases, it may take longer for the heart rate pattern to return to baseline if the fetus is preterm with growth restriction.

Placental abruption may occur after the convulsion and should be suspected if fetal bradycardia or repetitive late decelerations persist (FIGURE 2).

FIGURE 1 Fetal response to a convulsion The top 2 tracings show fetal bradycardia during an eclamptic convulsion

FIGURE 2 Abruptio placentae Repetitive late decelerations secondary to abruptio placentae, necessitating cesarean section

Uterine activity

During a convulsion, contractions can increase in frequency and tone. The duration of increased uterine activity varies from 2 to 14 minutes.

These changes usually resolve spontaneously within 3 to 10 minutes following the termination of convulsions and correction of maternal hypoxemia (FIGURE 1).

If uterine hyperactivity persists, suspect placental abruption (FIGURE 2).

Do not rush to cesarean

It benefits the fetus to allow in utero recovery from the maternal convulsion, hypoxia, and hypercarbia before delivery. However, if the bradycardia and/or recurrent late decelerations persist beyond 10 to 15 minutes despite all efforts, suspect abruptio placentae or nonreassuring fetal status.

Once the patient regains consciousness and is oriented to name, place, and time, and her convulsions are controlled and condition stabilized, proceed with delivery.

Choosing a delivery route

Eclampsia is not an indication for cesarean. The decision to perform a cesarean should be based on fetal gestational age, fetal condition, presence of labor, and cervical Bishop score. I recommend:

• Cesarean section for women with eclampsia before 30 weeks’ gestation who are not in labor and whose Bishop score is below 5.
• Vaginal delivery for women in labor or with rupture of membranes, provided there are no obstetric complications.
• Labor induction with oxytocin infusion or prostaglandins in all women at or after 30 weeks, regardless of the Bishop score, and in women before 30 weeks when the Bishop score is 5 or above.

Maternal pain relief

During labor and delivery, systemic opioids or epidural anesthesia can provide pain relief—the same recommendations as for women with severe preeclampsia.

For cesarean delivery, an epidural, spinal, or combined techniques of regional anesthesia are suitable.

Do not use regional anesthesia if there is coagulopathy or severe thrombocytopenia (platelet count less than 50,000/mm³). In women with eclampsia, general anesthesia increases the risk of aspiration and failed intubation due to airway edema, and is associated with marked increases in systemic and cerebral pressures during intubation and extubation.

Women with airway or laryngeal edema may require awake intubation under fiber optic observation, with tracheostomy immediately available.

Changes in systemic or cerebral pressures may be attenuated by pretreatment with labetalol or nitroglycerine injections.

Postpartum management

After delivery, women with eclampsia require close monitoring of vital signs, fluid intake and output, and symptoms for at least 48 hours.

Risk of pulmonary edema

These women usually receive large amounts of intravenous fluids during labor, delivery, and postpartum. In addition, during the postpartum period, extracellular fluid mobilizes, leading to increased intravascular volume.

As a result, women who develop eclampsia—particularly those with abnormal renal function, abruptio placentae, and/or preexisting chronic hypertension— face an increased risk for pulmonary edema and exacerbation of severe hypertension.²

Frequent evaluation of the amount of intravenous fluids is necessary, as well as oral intake, blood products, and urine output. They also need pulse oximetry and pulmonary auscultation.

Continue magnesium sulfate

Parenteral magnesium sulfate should be given for at least 24 hours after delivery and/or for at least 24 hours after the last convulsion.

If the patient has oliguria (less than 100 mL over 4 hours), both fluid administration and the dose of magnesium sulfate should be reduced.

Oral antihypertensives

Other oral antihypertensive agents such as labetalol or nifedipine can be given to keep systolic blood pressure below 155 mm Hg and diastolic blood pressure below 105 mm Hg. Nifedipine offers the benefit of improved diuresis in the postpartum period.

The author reports no financial relationships relevant to this article.

An eclamptic convulsion is frightening to behold. First, the woman’s face becomes distorted, and her eyes protrude. Then her face acquires a congested expression, and foam may exude from her mouth. Breathing stops.

Because eclampsia is so frightening, the natural tendency is to try to stop a convulsion, but this is not the wisest strategy.

Rather, the foremost priorities are to avoid maternal injury and support cardiovascular functions. How to do this, and how to prevent further convulsions, monitor and deliver the fetus, and avert complications are the focus of this article.

Since eclampsia may be fatal for both mother and fetus, all labor and delivery units and all obstetricians should be prepared to diagnose and manage this grave threat. However, few obstetric units encounter more than 1 or 2 cases a year; most obstetricians have little or no experience managing acute eclampsia. In the Western world, it affects only 1 in 2,000 to 1 in 3,448 pregnancies.^1-4

How a convulsion happens

Most convulsions occur in 2 phases and last for 60 to 75 seconds. The first phase, lasting 15 to 20 seconds, begins with facial twitching, soon followed by a rigid body with generalized muscular contractions.

In the second phase, which lasts about a minute, the muscles of the body alternately contract and relax in rapid succession. This phase begins with the muscles of the jaw and rapidly encompasses eyelids, other facial muscles, and body. If the tongue is unprotected, the woman often bites it.

Coma sometimes follows the convulsion, and deep, rapid breathing usually begins as soon as the convulsion stops. In fact, maintaining oxygenation typically is not a problem after a single convulsion, and the risk of aspiration is low in a well managed patient.

Upon reviving, the woman typically remembers nothing about the seizure.

If convulsions recur, some degree of consciousness returns after each one, although the woman may become combative, agitated, and difficult to control.

Harbingers of complications

In the developed world, eclampsia increases the risk of maternal death (range: 0 to 1.8%).^1-5 A recent review of all reported pregnancy-related deaths in the United States from 1979 to 1992 found 4,024 cases.⁶ Of these, 790 (19.6%) were due to preeclampsia-eclampsia, 49% of which were caused by eclampsia. The risk of death from preeclampsia or eclampsia was higher for the following groups:

• women over 30,
• no prenatal care,
• African Americans, and
• onset of preeclampsia or eclampsia before 28 weeks.⁶

Maternal morbidity

Pregnancies complicated by eclampsia also have higher rates of maternal morbidity such as pulmonary edema and HELLP syndrome (TABLE 1). Complications are substantially higher among women who develop antepartum eclampsia, especially when it is remote from term.^1-3

TABLE 1

Maternal complications

Antepartum eclampsia, especially when it is remote from term, is much more likely to lead to complications

Adverse perinatal outcomes

Perinatal mortality and morbidity are high in eclampsia, with a perinatal death rate in recent series of 5.6% to 11.8%.^1,7 This high rate is related to prematurity, abruptio placentae, and severe growth restriction.¹

Preterm deliveries occur in approximately 50% of cases, and about 25% occur before 32 weeks’ gestation.¹

Diagnosis can be tricky

When the patient has generalized edema, hypertension, proteinuria, and convulsions, diagnosis of eclampsia is straightforward. Unfortunately, women with eclampsia exhibit a broad spectrum of signs, ranging from severe hypertension, severe proteinuria, and generalized edema, to absent or minimal hypertension, nonexistent proteinuria, and no edema (TABLE 2).¹

Hypertension is the hallmark of diagnosis. Hypertension is severe (at least 160 mm Hg systolic and/or at least 110 mm Hg diastolic) in 20% to 54% of cases, and it is mild (systolic pressure between 140 and 160 mm Hg or diastolic pressure between 90 and 110 mm Hg) in 30% to 60% of cases.^2,3 In 16% of cases, there may be no hypertension at all.²

Proteinuria. Eclampsia usually is associated with proteinuria (at least 1+ on dipstick).¹ However, when I studied a series of 399 women with eclampsia, I found substantial proteinuria (3+ or above on dipstick) in only 48% of cases; proteinuria was absent in 14%.²

Edema. A weight gain of more than 2 lb per week (with or without clinical edema) during the third trimester may be the first sign of eclampsia. However, in my series of 399 women, edema was absent in 26% of cases.²

TABLE 2

Signs and symptoms of eclampsia*

Hypertension and proteinuria in eclampsia may be severe, mild, or even absent

Symptoms of eclampsia

Several clinical symptoms can occur before or after a convulsion¹:

• persistent occipital or frontal headaches,
• blurred vision,
• photophobia,
• epigastric and/or right upper quadrant pain, and
• altered mental status.

Usual times of onset

Eclamptic convulsions can occur during pregnancy or delivery, or after delivery ( TABLE 3).^1-5

Approximately 91% of antepartum cases develop at 28 weeks or beyond. The remaining cases tend to occur between 21 and 27 weeks’ gestation (7.5%), or at or before 20 weeks (1.5%).²

When eclampsia occurs before 20 weeks, it usually involves molar or hydropic degeneration of the placenta, with or without a fetus.¹ However, eclampsia can occur in the first half of pregnancy without molar degeneration of the placenta, although this is rare.^1,2 These women are sometimes misdiagnosed as having hypertensive encephalopathy, seizure disorder, or thrombotic thrombocytopenia purpura. Thus, women who develop convulsions in association with hypertension and proteinuria in the first half of pregnancy should be assumed to have eclampsia until proven otherwise,¹ and require ultrasound examination of the uterus to rule out molar pregnancy and/or hydropic or cystic degeneration of the placenta.

Postpartum cases tend to occur within the first 48 hours, although some develop beyond this limit and have been reported as late as 23 days postpartum.⁸

Late postpartum eclampsia occurs more than 48 hours but less than 4 weeks after delivery.⁸ These women have signs and symptoms consistent with preeclampsia along with their convulsions.^8,9 Thus, women who develop convulsions with hypertension and/or proteinuria, or with headaches or blurred vision, after 48 hours postpartum should be assumed to have eclampsia and treated accordingly.^8,9

When eclampsia occurs especially late, perform an extensive neurologic examination to rule out other cerebral pathology.^1,10

Eclampsia is atypical if convulsions occur before 20 weeks’ gestation or beyond 48 hours postpartum. It also is atypical if convulsions develop or persist despite adequate magnesium sulfate, or if the patient develops focal neurologic deficits, disorientation, blindness, or coma. In these cases, conduct a neurologic exam and cerebral imaging to exclude neurologic pathology.^8-10

TABLE 3

Usual times of onset*

91% of antepartum eclampsia cases occur at 28 weeks or later, although eclamptic convulsions can occur at any time during pregnancy or delivery, or postpartum

Differential diagnosis

As with other aspects of preeclampsia, the presenting symptoms, clinical findings, and many laboratory results in eclampsia overlap several other medical and surgical conditions.^1,10 Of course, eclampsia is the most common cause of convulsions in a woman with hypertension and/or proteinuria during pregnancy or immediately postpartum. On rare occasions, other causes of convulsions in pregnancy or postpartum may mimic eclampsia.¹ These potential diagnoses are particularly important when the woman has focal neurologic deficits, prolonged coma, or atypical eclampsia.

The differential diagnosis encompasses a variety of cerebrovascular and metabolic disorders:

• hemorrhage,
• ruptured aneurysm or malformation,
• arterial embolism, thrombosis,
• venous thrombosis,
• hypoxic ischemic encephalopathy,
• angiomas,
• hypertensive encephalopathy,
• seizure disorder,
• hypoglycemia, hyponatremia,
• posterior leukoencephalopathy syndrome,
• thrombotic thrombocytopenic purpura,
• postdural puncture syndrome, and
• cerebral vasculitis/angiopathy.

Other diseases may factor in

Some women develop gestational hypertension or preeclampsia in association with connective tissue disease, thrombophilias, seizure disorder, or hypertensive encephalopathy, further confounding the diagnosis.

Thus, make every effort to ensure a correct diagnosis, since management may differ among these conditions.

Managing convulsions

Do not try to stop the first convulsion

The natural tendency is to try and interrupt the convulsion, but this is not recommended. Nor should you give a drug such as diazepam to shorten or stop the convulsion, especially if the patient lacks an intravenous line and no one skilled in intubation is immediately available. If diazepam is given, do not exceed 5 mg over 60 seconds. Rapid administration of this drug may lead to apnea or cardiac arrest, or both.

Steps to prevent maternal injury

During or immediately after the acute convulsive episode, take steps to prevent serious maternal injury and aspiration, assess and establish airway patency, and ensure maternal oxygenation (TABLE 4).

Elevate and pad the bed’s side rails and insert a padded tongue blade between the patient’s teeth, taking care not to trigger the gag reflex.

Physical restraints also may be needed.

Prevent aspiration. To minimize the risk of aspiration, place the patient in the lateral decubitus position, and suction vomitus and oral secretions as needed. Be aware that aspiration can occur when the padded tongue blade is forced to the back of the throat, stimulating the gag reflex and resultant vomiting.

TABLE 4

During a convulsion, 3 spheres of concern

Tips on supplemental oxygenation

Although the initial seizure lasts only a minute or 2, it is important to maintain oxygenation by giving supplemental oxygen via a face mask, with or without an oxygen reservoir, at 8 to 10 L per minute. This is important because hypoventilation and respiratory acidosis often occur.

Once the convulsion ends and the patient resumes breathing, oxygenation is rarely a problem. However, maternal hypoxemia and acidosis can develop in women with repetitive convulsions, aspiration pneumonia, pulmonary edema, or a combination of these factors. Thus, transcutaneous pulse oximetry is advisable to monitor oxygenation in eclamptic patients.

Arterial blood gas analysis is necessary if pulse oximetry shows abnormal oxygen saturation (ie, at or below 92%).

Strategy to prevent recurrence

Magnesium sulfate is the drug of choice to treat and prevent subsequent convulsions in women with eclampsia.^1,2

Dosage. I give a loading dose of 6 g over 15 to 20 minutes, followed by a maintenance dose of 2 g per hour as a continuous intravenous solution.

Approximately 10% of eclamptic women have a second convulsion after receiving magnesium sulfate.^1,2 When this occurs, I give another 2-g bolus intravenously over 3 to 5 minutes.

More rarely, a woman will continue to have convulsions while receiving adequate and therapeutic doses of magnesium sulfate.

I treat such patients with sodium amobarbital, 250 mg, intravenously over 3 to 5 minutes.

Monitor maternal magnesium levels

Plasma levels should be in the range of 4 to 8 mg/dL during treatment for eclampsia, and are determined by the volume of distribution and by renal excretion. Thus, it is important to monitor the patient for magnesium toxicity, particularly if she has renal dysfunction (serum creatinine of 1.2 mg/dL or above) or urine output below 100 mL in 4 hours. In these women, adjust the maintenance dose according to plasma levels.

Side effects of magnesium including flushing, a feeling of warmth, nausea and vomiting, double vision, and slurred speech (TABLE 5).

If magnesium toxicity is suspected, immediately discontinue the infusion and administer supplemental oxygen along with 10 mL of 10% calcium gluconate (1 g total) as an intravenous push slowly over 5 minutes.

If respiratory arrest occurs, prompt resuscitation—including intubation and assisted ventilation—is vital.

TABLE 5

Clinical manifestations of magnesium toxicity

Maternal plasma levels of 4 to 8 mg/dL are appropriate during treatment for eclampsia; higher levels signal toxicity

Controlling severe hypertension

The next step is to reduce blood pressure to a safe range. The objective: to preserve cerebral autoregulation and prevent congestive heart failure without compromising cerebral perfusion or jeopardizing uteroplacental blood flow, which is already reduced in many women with eclampsia.¹

To these ends, try to keep systolic blood pressure between 140 and 160 mm Hg and diastolic pressure between 90 and 110 mm Hg. This can be achieved with:

• bolus 5- to 10-mg doses of hydralazine,
• 20 to 40 mg labetalol intravenously every 15 minutes, as needed, or
• 10 to 20 mg oral nifedipine every 30 minutes.

Other potent antihypertensive drugs such as sodium nitroprusside or nitroglycerine are rarely needed in eclampsia, and diuretics are indicated only in the presence of pulmonary edema.

Intrapartum management

Maternal hypoxemia and hypercarbia cause fetal heart rate and uterine activity changes during and immediately following a convulsion.

Fetal heart rate changes

These can include bradycardia, transient late decelerations, decreased beat-to-beat variability, and compensatory tachycardia.

The interval from onset of the seizure to the fall in fetal heart rate is approximately 5 minutes (FIGURE 1). Transitory fetal tachycardia frequently occurs after the prolonged bradycardia. The loss of beat-to-beat variability, with transitory late decelerations, occurs during the recovery phase.

The mechanism for the transient fetal bradycardia may be intense vasospasm and uterine hyperactivity, which may decrease uterine blood flow. The absence of maternal respiration during the convulsion may also contribute to fetal heart rate changes.

Since the fetal heart rate usually returns to normal after a convulsion, other conditions should be considered if an abnormal pattern persists.

In some cases, it may take longer for the heart rate pattern to return to baseline if the fetus is preterm with growth restriction.

Placental abruption may occur after the convulsion and should be suspected if fetal bradycardia or repetitive late decelerations persist (FIGURE 2).

FIGURE 1 Fetal response to a convulsion The top 2 tracings show fetal bradycardia during an eclamptic convulsion

FIGURE 2 Abruptio placentae Repetitive late decelerations secondary to abruptio placentae, necessitating cesarean section

Uterine activity

During a convulsion, contractions can increase in frequency and tone. The duration of increased uterine activity varies from 2 to 14 minutes.

These changes usually resolve spontaneously within 3 to 10 minutes following the termination of convulsions and correction of maternal hypoxemia (FIGURE 1).

If uterine hyperactivity persists, suspect placental abruption (FIGURE 2).

Do not rush to cesarean

It benefits the fetus to allow in utero recovery from the maternal convulsion, hypoxia, and hypercarbia before delivery. However, if the bradycardia and/or recurrent late decelerations persist beyond 10 to 15 minutes despite all efforts, suspect abruptio placentae or nonreassuring fetal status.

Once the patient regains consciousness and is oriented to name, place, and time, and her convulsions are controlled and condition stabilized, proceed with delivery.

Choosing a delivery route

Eclampsia is not an indication for cesarean. The decision to perform a cesarean should be based on fetal gestational age, fetal condition, presence of labor, and cervical Bishop score. I recommend:

• Cesarean section for women with eclampsia before 30 weeks’ gestation who are not in labor and whose Bishop score is below 5.
• Vaginal delivery for women in labor or with rupture of membranes, provided there are no obstetric complications.
• Labor induction with oxytocin infusion or prostaglandins in all women at or after 30 weeks, regardless of the Bishop score, and in women before 30 weeks when the Bishop score is 5 or above.

Maternal pain relief

During labor and delivery, systemic opioids or epidural anesthesia can provide pain relief—the same recommendations as for women with severe preeclampsia.

For cesarean delivery, an epidural, spinal, or combined techniques of regional anesthesia are suitable.

Do not use regional anesthesia if there is coagulopathy or severe thrombocytopenia (platelet count less than 50,000/mm³). In women with eclampsia, general anesthesia increases the risk of aspiration and failed intubation due to airway edema, and is associated with marked increases in systemic and cerebral pressures during intubation and extubation.

Women with airway or laryngeal edema may require awake intubation under fiber optic observation, with tracheostomy immediately available.

Changes in systemic or cerebral pressures may be attenuated by pretreatment with labetalol or nitroglycerine injections.

Postpartum management

After delivery, women with eclampsia require close monitoring of vital signs, fluid intake and output, and symptoms for at least 48 hours.

Risk of pulmonary edema

These women usually receive large amounts of intravenous fluids during labor, delivery, and postpartum. In addition, during the postpartum period, extracellular fluid mobilizes, leading to increased intravascular volume.

As a result, women who develop eclampsia—particularly those with abnormal renal function, abruptio placentae, and/or preexisting chronic hypertension— face an increased risk for pulmonary edema and exacerbation of severe hypertension.²

Frequent evaluation of the amount of intravenous fluids is necessary, as well as oral intake, blood products, and urine output. They also need pulse oximetry and pulmonary auscultation.

Continue magnesium sulfate

Parenteral magnesium sulfate should be given for at least 24 hours after delivery and/or for at least 24 hours after the last convulsion.

If the patient has oliguria (less than 100 mL over 4 hours), both fluid administration and the dose of magnesium sulfate should be reduced.

Oral antihypertensives

Other oral antihypertensive agents such as labetalol or nifedipine can be given to keep systolic blood pressure below 155 mm Hg and diastolic blood pressure below 105 mm Hg. Nifedipine offers the benefit of improved diuresis in the postpartum period.

The author reports no financial relationships relevant to this article.

Many gynecologists now recognize that surgery is of little benefit in the initial diagnosis and treatment of the syndrome of chronic pelvic pain, but effective alternatives have not been well established either. Within the last year, however, new research has given us a better understanding of its causes, evaluation, and management. This Update discusses new findings on the following patient care issues:

• How a common nerve pathway may affect chronic pelvic pain patterns
  
• Transvaginal ultrasound in the evaluation of acute versus chronic pelvic pain
  
• The placebo effect of surgery
  
• What we can and cannot expect from endometriosis resection
  
• The role of adhesions in pain
  
• Limits of hysterectomy
  
• Medical therapy
  

Any nerve plexus injury may lead to pain

Quinn M. Obstetric denervation–gynaecological reinnervation: disruption of the inferior hypogastric plexus in childbirth as a source of gynaecological symptoms. Med Hypoth. 2004;63:390–393.

When we fit together the pieces of the chronic pelvic pain puzzle, a picture emerges that suggests the pelvic organs are connected functionally, not just by anatomical proximity. Recent commercial promotion of drugs for diseases of the bladder and bowel has raised our awareness of interstitial cystitis and irritable bowel syndrome as factors in chronic pelvic pain, and we recognize that bowel and bladder symptoms often accompany gynecologic symptoms, such as dysmenorrhea and vulvodynia. Now, a hypothesis introduced by Martin Quinn suggests disruption of the inferior hypogastric nervous plexus during childbirth may result in reinnervation changes that cause visceral pain years later. He found collateral nervesprouting and a chaotic distribution of nerve fibers when special stains were used on surgical specimens.

According to this hypothesis:

• Cesarean section is not the answer to this childbirth-related injury, because cesarean section injures the nerve plexus.
  
• Hysterectomy would be effective for chronic pain only if abnormal nerve regeneration is restricted to the uterus.
  

DIAGNOSISUltrasound is more useful for acute than chronic pain

Clinicians are taught that a good history and physical examination are the most important diagnostic tools in evaluating symptoms, but we often use imaging studies as well, including routine transvaginal ultrasound in the evaluation of pelvic pain. This analysis of published studies identified transvaginal ultrasound as an extension of the bimanual exam, but observed its greatest utility for acute rather than chronic pelvic pain. In chronic pelvic pain, laparoscopic findings, if abnormal, commonly include endometriosis and adhesions—for which transvaginal ultrasound is not very useful unless there is fixation or enlargement of the ovary.

This review describes use of ultrasound for identification of heterogeneous myometrial echotexture, asymmetric uterine enlargement, and subendometrial cysts as features of adenomyosis, and reports a positive predictive value of 68% to 86% in published series.

SURGERYExcision can be effective—so can sham surgery

Some gynecologists still choose surgery as a first-line treatment, although a landmark randomized trial published 14 years ago proved that a nonsurgical approach more effectively resolves chronic pelvic pain symptoms.¹ The enthusiasm for surgery is highest when endometriosis is suspected, and some gynecologists still believe that the only adequate treatment is physical removal or destruction of implants.

Pain relief has been attributed to laparoscopic treatment of endometriosis, but cause-and-effect is uncertain, in part because of confounding factors.

For example, in a report on outcomes after ablative therapy for stage 3 or 4 endometriosis with endometriotic cysts, Jones and Sutton² considered surgery successful because 87.7% of subjects were satisfied 1 year later. This interpretation can be questioned, however, given that patients who did not want to conceive were treated with oral contraceptives or gonadotropin-releasing hormone analog after surgery. The extent to which symptoms responded to the medication rather than the surgery is not known.

Also unknown is the extent to which symptoms respond to the placebo effect of surgery. Sutton and colleagues had previously shown that pain relief 3 months after laser laparoscopy was no greater than after sham surgery,³ but by 6 months, pain relief in the sham surgery group was not sustained, and was lower than in the real surgery group.

The new study by Abbott et al re-addressed the placebo effect of surgery by randomizing 39 women with pain and visible endometriosis implants to either diagnostic laparoscopy or laparoscopic excision of endometriosis. Six months after the surgery, the women had a second laparoscopic procedure during which the extent of endometriosis was reevaluated and visible disease was resected. In other words, all women had resection of endometriosis, although in half of the subjects, the resection was preceded by a sham operation.

Six months after the first operation, 80% of the resection group said they were improved, compared to 32% of the sham surgery group. Six months after the second operation, 83% of those who initially had sham surgery were improved.

This study shows that surgical resection can be effective in reducing pain associated with visible endometriosis, but there are 2 important additional findings:

• The placebo response of 32% is considerable and not to be ignored.
  
• Despite aggressive excisional surgery with its risks of major organ injury, up to 20% of subjects did not improve.
  

Is adhesiolysis helpful or not?

Hammoud A, Gago A, Diamond MP. Adhesions in patients with chronic pelvic pain: a role for adhesiolysis? Fertil Steril. 2004;82:1483–1491.

Adhesions may be blamed for chronic pelvic pain, although randomized trials have shown adhesiolysis no more effective than sham surgery.^4,5 Hammoud et al hypothesized that adhesions cause pain when they distort normal anatomy and pull on peritoneum, but stress that this idea has not been validated.

Their study found substantial evidence against the theory that adhesions cause pain, and suggests that pain and adhesions may both be due to an underlying process such as endometriosis.

They also review the evidence on the important complications that may occur with attempted surgical adhesiolysis.

Hysterectomy less helpful with preop depression

Hartmann KE, Ma C, Lamvu GM, Langenberg PW, Steege JF, Kjerulff KH. Quality of life and sexual function after hysterectomy in women with preoperative pain and depression. Obstet Gynecol. 2004;104:701–709.

Some gynecologists use removal of the uterus as the definitive treatment for chronic pain, although no controlled studies have examined the effectiveness of this operation compared to nonsurgical treatments. Hartmann et al evaluated quality of life and sexual function after hysterectomy in women who had pain, depression, or both pain and depression prior to surgery.

Results were compared between these groups and with women who had neither pain nor depression before surgery. Women with both pain and depression were more likely to have impaired quality of life after hysterectomy than were women with pain or depression alone or women with neither pain nor depression.

Two years later, pelvic pain was still troubling 19.4% of women with preoperative depression and pain, and only 9.3% of women with preoperative pain only.

Hysterectomy led to improvement in many quality of life measures and sexual function in women with pain, depression, or both. The authors concluded, “Overall we do not do harm when we perform hysterectomy for these complex patients.”

That conclusion, however, fails to consider surgical complications, time lost from work or other activities, or monetary costs, which were not evaluated.

There was no nonsurgical comparison group, and the authors point out that their study did not address the possibility that nonsurgical treatments may be as effective or more effective than hysterectomy.

REFERENCES

1. Peters AAW, van Dorst E, Jellis B, van Zuuren E, Hermans J, Trimbos JB. A randomized trial to compare 2 different approaches to women with chronic pelvic pain. Obstet Gynecol. 1991;77:740-744.

2. Jones KD, Sutton C. Patient satisfaction and changes in pain scores after ablative laparoscopic surgery for stage III–IV endometriosis and endometriotic cysts. Fertil Steril. 2003;79:1086-1090.

3. Sutton CJG, Ewen SP, Whitelaw N, Haines P. Prospective, randomized, double-blind controlled trial of laser laparoscopy in the treatment of pelvic pain associated with minimal, mild and moderate endometriosis. Fertil Steril. 1994;62:696-700.

4. Peters AAW, Trimbos-Kemper GCM, Admiral C, Trimbos JB. A randomized clinical trial on the benefit of adhesiolysis in patients with intraperitoneal adhesions and chronic pelvic pain. Br J Obstet Gynaecol. 1992;99:59-62.

5. Swank DJ, Swank-Bordewijk SC, Hop WC, et al. Laparoscopic adhesiolysis in patients with chronic abdominal pain: a blinded randomized controlled multi-centre trial. Lancet. 2003;361:1247-1251.

MEDICAL THERAPYLetrozole for endometriosis?

The discovery that endometriosis implants may contain the aromatase enzyme prompted consideration of aromatase inhibitors as a nonsurgical treatment for endometriosis. These agents, which prevent conversion of androgens to estrogens, are used in the management of breast cancer.

This pilot study evaluated the use of the aromatase inhibitor letrozole in 10 women in whom medical and surgical therapy for endometriosis had failed. Addback therapy with norethindrone acetate was given to prevent the decrease in bone mineral density that might have occurred with letrozole alone. In 9 of the 10 women, pain decreased over the 6 months of the study.

This encouraging result suggests that larger trials with control subjects and longer follow-up will be worthwhile.

Recommendation: Use GnRH agonist

Nasir L, Bope ET. Management of pelvic pain from dysmenorrhea or endometriosis. J Am Board Fam Pract. 2004;17:S43–S47.

Recommendations from the Family Practice Pain Education Project published at the end of 2004 support use of nonsurgical therapies for endometriosis, based in part on the findings of Ling et al,¹ which demonstrated the effectiveness of empirical therapy.

ACOG agrees

That recommendation is similar to the nonsurgical approach to chronic pelvic pain recommended in 1999 in an ACOG Practice Bulletin²:

“Therapy with a GnRH agonist is an appropriate approach to the management of women with chronic pelvic pain, even in the absence of surgical confirmation of endometriosis, provided that a detailed initial evaluation fails to demonstrate some other cause of pelvic pain.”

The author is a speaker and consultant for TAP Pharmaceuticals.

Many gynecologists now recognize that surgery is of little benefit in the initial diagnosis and treatment of the syndrome of chronic pelvic pain, but effective alternatives have not been well established either. Within the last year, however, new research has given us a better understanding of its causes, evaluation, and management. This Update discusses new findings on the following patient care issues:

• How a common nerve pathway may affect chronic pelvic pain patterns
  
• Transvaginal ultrasound in the evaluation of acute versus chronic pelvic pain
  
• The placebo effect of surgery
  
• What we can and cannot expect from endometriosis resection
  
• The role of adhesions in pain
  
• Limits of hysterectomy
  
• Medical therapy
  

Any nerve plexus injury may lead to pain

Quinn M. Obstetric denervation–gynaecological reinnervation: disruption of the inferior hypogastric plexus in childbirth as a source of gynaecological symptoms. Med Hypoth. 2004;63:390–393.

When we fit together the pieces of the chronic pelvic pain puzzle, a picture emerges that suggests the pelvic organs are connected functionally, not just by anatomical proximity. Recent commercial promotion of drugs for diseases of the bladder and bowel has raised our awareness of interstitial cystitis and irritable bowel syndrome as factors in chronic pelvic pain, and we recognize that bowel and bladder symptoms often accompany gynecologic symptoms, such as dysmenorrhea and vulvodynia. Now, a hypothesis introduced by Martin Quinn suggests disruption of the inferior hypogastric nervous plexus during childbirth may result in reinnervation changes that cause visceral pain years later. He found collateral nervesprouting and a chaotic distribution of nerve fibers when special stains were used on surgical specimens.

According to this hypothesis:

• Cesarean section is not the answer to this childbirth-related injury, because cesarean section injures the nerve plexus.
  
• Hysterectomy would be effective for chronic pain only if abnormal nerve regeneration is restricted to the uterus.
  

DIAGNOSISUltrasound is more useful for acute than chronic pain

Clinicians are taught that a good history and physical examination are the most important diagnostic tools in evaluating symptoms, but we often use imaging studies as well, including routine transvaginal ultrasound in the evaluation of pelvic pain. This analysis of published studies identified transvaginal ultrasound as an extension of the bimanual exam, but observed its greatest utility for acute rather than chronic pelvic pain. In chronic pelvic pain, laparoscopic findings, if abnormal, commonly include endometriosis and adhesions—for which transvaginal ultrasound is not very useful unless there is fixation or enlargement of the ovary.

This review describes use of ultrasound for identification of heterogeneous myometrial echotexture, asymmetric uterine enlargement, and subendometrial cysts as features of adenomyosis, and reports a positive predictive value of 68% to 86% in published series.

SURGERYExcision can be effective—so can sham surgery

Some gynecologists still choose surgery as a first-line treatment, although a landmark randomized trial published 14 years ago proved that a nonsurgical approach more effectively resolves chronic pelvic pain symptoms.¹ The enthusiasm for surgery is highest when endometriosis is suspected, and some gynecologists still believe that the only adequate treatment is physical removal or destruction of implants.

Pain relief has been attributed to laparoscopic treatment of endometriosis, but cause-and-effect is uncertain, in part because of confounding factors.

For example, in a report on outcomes after ablative therapy for stage 3 or 4 endometriosis with endometriotic cysts, Jones and Sutton² considered surgery successful because 87.7% of subjects were satisfied 1 year later. This interpretation can be questioned, however, given that patients who did not want to conceive were treated with oral contraceptives or gonadotropin-releasing hormone analog after surgery. The extent to which symptoms responded to the medication rather than the surgery is not known.

Also unknown is the extent to which symptoms respond to the placebo effect of surgery. Sutton and colleagues had previously shown that pain relief 3 months after laser laparoscopy was no greater than after sham surgery,³ but by 6 months, pain relief in the sham surgery group was not sustained, and was lower than in the real surgery group.

The new study by Abbott et al re-addressed the placebo effect of surgery by randomizing 39 women with pain and visible endometriosis implants to either diagnostic laparoscopy or laparoscopic excision of endometriosis. Six months after the surgery, the women had a second laparoscopic procedure during which the extent of endometriosis was reevaluated and visible disease was resected. In other words, all women had resection of endometriosis, although in half of the subjects, the resection was preceded by a sham operation.

Six months after the first operation, 80% of the resection group said they were improved, compared to 32% of the sham surgery group. Six months after the second operation, 83% of those who initially had sham surgery were improved.

This study shows that surgical resection can be effective in reducing pain associated with visible endometriosis, but there are 2 important additional findings:

• The placebo response of 32% is considerable and not to be ignored.
  
• Despite aggressive excisional surgery with its risks of major organ injury, up to 20% of subjects did not improve.
  

Is adhesiolysis helpful or not?

Hammoud A, Gago A, Diamond MP. Adhesions in patients with chronic pelvic pain: a role for adhesiolysis? Fertil Steril. 2004;82:1483–1491.

Adhesions may be blamed for chronic pelvic pain, although randomized trials have shown adhesiolysis no more effective than sham surgery.^4,5 Hammoud et al hypothesized that adhesions cause pain when they distort normal anatomy and pull on peritoneum, but stress that this idea has not been validated.

Their study found substantial evidence against the theory that adhesions cause pain, and suggests that pain and adhesions may both be due to an underlying process such as endometriosis.

They also review the evidence on the important complications that may occur with attempted surgical adhesiolysis.

Hysterectomy less helpful with preop depression

Hartmann KE, Ma C, Lamvu GM, Langenberg PW, Steege JF, Kjerulff KH. Quality of life and sexual function after hysterectomy in women with preoperative pain and depression. Obstet Gynecol. 2004;104:701–709.

Some gynecologists use removal of the uterus as the definitive treatment for chronic pain, although no controlled studies have examined the effectiveness of this operation compared to nonsurgical treatments. Hartmann et al evaluated quality of life and sexual function after hysterectomy in women who had pain, depression, or both pain and depression prior to surgery.

Results were compared between these groups and with women who had neither pain nor depression before surgery. Women with both pain and depression were more likely to have impaired quality of life after hysterectomy than were women with pain or depression alone or women with neither pain nor depression.

Two years later, pelvic pain was still troubling 19.4% of women with preoperative depression and pain, and only 9.3% of women with preoperative pain only.

Hysterectomy led to improvement in many quality of life measures and sexual function in women with pain, depression, or both. The authors concluded, “Overall we do not do harm when we perform hysterectomy for these complex patients.”

That conclusion, however, fails to consider surgical complications, time lost from work or other activities, or monetary costs, which were not evaluated.

There was no nonsurgical comparison group, and the authors point out that their study did not address the possibility that nonsurgical treatments may be as effective or more effective than hysterectomy.

REFERENCES

1. Peters AAW, van Dorst E, Jellis B, van Zuuren E, Hermans J, Trimbos JB. A randomized trial to compare 2 different approaches to women with chronic pelvic pain. Obstet Gynecol. 1991;77:740-744.

2. Jones KD, Sutton C. Patient satisfaction and changes in pain scores after ablative laparoscopic surgery for stage III–IV endometriosis and endometriotic cysts. Fertil Steril. 2003;79:1086-1090.

3. Sutton CJG, Ewen SP, Whitelaw N, Haines P. Prospective, randomized, double-blind controlled trial of laser laparoscopy in the treatment of pelvic pain associated with minimal, mild and moderate endometriosis. Fertil Steril. 1994;62:696-700.

4. Peters AAW, Trimbos-Kemper GCM, Admiral C, Trimbos JB. A randomized clinical trial on the benefit of adhesiolysis in patients with intraperitoneal adhesions and chronic pelvic pain. Br J Obstet Gynaecol. 1992;99:59-62.

5. Swank DJ, Swank-Bordewijk SC, Hop WC, et al. Laparoscopic adhesiolysis in patients with chronic abdominal pain: a blinded randomized controlled multi-centre trial. Lancet. 2003;361:1247-1251.

MEDICAL THERAPYLetrozole for endometriosis?

The discovery that endometriosis implants may contain the aromatase enzyme prompted consideration of aromatase inhibitors as a nonsurgical treatment for endometriosis. These agents, which prevent conversion of androgens to estrogens, are used in the management of breast cancer.

This pilot study evaluated the use of the aromatase inhibitor letrozole in 10 women in whom medical and surgical therapy for endometriosis had failed. Addback therapy with norethindrone acetate was given to prevent the decrease in bone mineral density that might have occurred with letrozole alone. In 9 of the 10 women, pain decreased over the 6 months of the study.

This encouraging result suggests that larger trials with control subjects and longer follow-up will be worthwhile.

Recommendation: Use GnRH agonist

Nasir L, Bope ET. Management of pelvic pain from dysmenorrhea or endometriosis. J Am Board Fam Pract. 2004;17:S43–S47.

Recommendations from the Family Practice Pain Education Project published at the end of 2004 support use of nonsurgical therapies for endometriosis, based in part on the findings of Ling et al,¹ which demonstrated the effectiveness of empirical therapy.

ACOG agrees

That recommendation is similar to the nonsurgical approach to chronic pelvic pain recommended in 1999 in an ACOG Practice Bulletin²:

“Therapy with a GnRH agonist is an appropriate approach to the management of women with chronic pelvic pain, even in the absence of surgical confirmation of endometriosis, provided that a detailed initial evaluation fails to demonstrate some other cause of pelvic pain.”

The author is a speaker and consultant for TAP Pharmaceuticals.

Many gynecologists now recognize that surgery is of little benefit in the initial diagnosis and treatment of the syndrome of chronic pelvic pain, but effective alternatives have not been well established either. Within the last year, however, new research has given us a better understanding of its causes, evaluation, and management. This Update discusses new findings on the following patient care issues:

• How a common nerve pathway may affect chronic pelvic pain patterns
  
• Transvaginal ultrasound in the evaluation of acute versus chronic pelvic pain
  
• The placebo effect of surgery
  
• What we can and cannot expect from endometriosis resection
  
• The role of adhesions in pain
  
• Limits of hysterectomy
  
• Medical therapy
  

Any nerve plexus injury may lead to pain

Quinn M. Obstetric denervation–gynaecological reinnervation: disruption of the inferior hypogastric plexus in childbirth as a source of gynaecological symptoms. Med Hypoth. 2004;63:390–393.

When we fit together the pieces of the chronic pelvic pain puzzle, a picture emerges that suggests the pelvic organs are connected functionally, not just by anatomical proximity. Recent commercial promotion of drugs for diseases of the bladder and bowel has raised our awareness of interstitial cystitis and irritable bowel syndrome as factors in chronic pelvic pain, and we recognize that bowel and bladder symptoms often accompany gynecologic symptoms, such as dysmenorrhea and vulvodynia. Now, a hypothesis introduced by Martin Quinn suggests disruption of the inferior hypogastric nervous plexus during childbirth may result in reinnervation changes that cause visceral pain years later. He found collateral nervesprouting and a chaotic distribution of nerve fibers when special stains were used on surgical specimens.

According to this hypothesis:

• Cesarean section is not the answer to this childbirth-related injury, because cesarean section injures the nerve plexus.
  
• Hysterectomy would be effective for chronic pain only if abnormal nerve regeneration is restricted to the uterus.
  

DIAGNOSISUltrasound is more useful for acute than chronic pain

Clinicians are taught that a good history and physical examination are the most important diagnostic tools in evaluating symptoms, but we often use imaging studies as well, including routine transvaginal ultrasound in the evaluation of pelvic pain. This analysis of published studies identified transvaginal ultrasound as an extension of the bimanual exam, but observed its greatest utility for acute rather than chronic pelvic pain. In chronic pelvic pain, laparoscopic findings, if abnormal, commonly include endometriosis and adhesions—for which transvaginal ultrasound is not very useful unless there is fixation or enlargement of the ovary.

This review describes use of ultrasound for identification of heterogeneous myometrial echotexture, asymmetric uterine enlargement, and subendometrial cysts as features of adenomyosis, and reports a positive predictive value of 68% to 86% in published series.

SURGERYExcision can be effective—so can sham surgery

Some gynecologists still choose surgery as a first-line treatment, although a landmark randomized trial published 14 years ago proved that a nonsurgical approach more effectively resolves chronic pelvic pain symptoms.¹ The enthusiasm for surgery is highest when endometriosis is suspected, and some gynecologists still believe that the only adequate treatment is physical removal or destruction of implants.

Pain relief has been attributed to laparoscopic treatment of endometriosis, but cause-and-effect is uncertain, in part because of confounding factors.

For example, in a report on outcomes after ablative therapy for stage 3 or 4 endometriosis with endometriotic cysts, Jones and Sutton² considered surgery successful because 87.7% of subjects were satisfied 1 year later. This interpretation can be questioned, however, given that patients who did not want to conceive were treated with oral contraceptives or gonadotropin-releasing hormone analog after surgery. The extent to which symptoms responded to the medication rather than the surgery is not known.

Also unknown is the extent to which symptoms respond to the placebo effect of surgery. Sutton and colleagues had previously shown that pain relief 3 months after laser laparoscopy was no greater than after sham surgery,³ but by 6 months, pain relief in the sham surgery group was not sustained, and was lower than in the real surgery group.

The new study by Abbott et al re-addressed the placebo effect of surgery by randomizing 39 women with pain and visible endometriosis implants to either diagnostic laparoscopy or laparoscopic excision of endometriosis. Six months after the surgery, the women had a second laparoscopic procedure during which the extent of endometriosis was reevaluated and visible disease was resected. In other words, all women had resection of endometriosis, although in half of the subjects, the resection was preceded by a sham operation.

Six months after the first operation, 80% of the resection group said they were improved, compared to 32% of the sham surgery group. Six months after the second operation, 83% of those who initially had sham surgery were improved.

This study shows that surgical resection can be effective in reducing pain associated with visible endometriosis, but there are 2 important additional findings:

• The placebo response of 32% is considerable and not to be ignored.
  
• Despite aggressive excisional surgery with its risks of major organ injury, up to 20% of subjects did not improve.
  

Is adhesiolysis helpful or not?

Hammoud A, Gago A, Diamond MP. Adhesions in patients with chronic pelvic pain: a role for adhesiolysis? Fertil Steril. 2004;82:1483–1491.

Adhesions may be blamed for chronic pelvic pain, although randomized trials have shown adhesiolysis no more effective than sham surgery.^4,5 Hammoud et al hypothesized that adhesions cause pain when they distort normal anatomy and pull on peritoneum, but stress that this idea has not been validated.

Their study found substantial evidence against the theory that adhesions cause pain, and suggests that pain and adhesions may both be due to an underlying process such as endometriosis.

They also review the evidence on the important complications that may occur with attempted surgical adhesiolysis.

Hysterectomy less helpful with preop depression

Hartmann KE, Ma C, Lamvu GM, Langenberg PW, Steege JF, Kjerulff KH. Quality of life and sexual function after hysterectomy in women with preoperative pain and depression. Obstet Gynecol. 2004;104:701–709.

Some gynecologists use removal of the uterus as the definitive treatment for chronic pain, although no controlled studies have examined the effectiveness of this operation compared to nonsurgical treatments. Hartmann et al evaluated quality of life and sexual function after hysterectomy in women who had pain, depression, or both pain and depression prior to surgery.

Results were compared between these groups and with women who had neither pain nor depression before surgery. Women with both pain and depression were more likely to have impaired quality of life after hysterectomy than were women with pain or depression alone or women with neither pain nor depression.

Two years later, pelvic pain was still troubling 19.4% of women with preoperative depression and pain, and only 9.3% of women with preoperative pain only.

Hysterectomy led to improvement in many quality of life measures and sexual function in women with pain, depression, or both. The authors concluded, “Overall we do not do harm when we perform hysterectomy for these complex patients.”

That conclusion, however, fails to consider surgical complications, time lost from work or other activities, or monetary costs, which were not evaluated.

There was no nonsurgical comparison group, and the authors point out that their study did not address the possibility that nonsurgical treatments may be as effective or more effective than hysterectomy.

REFERENCES

1. Peters AAW, van Dorst E, Jellis B, van Zuuren E, Hermans J, Trimbos JB. A randomized trial to compare 2 different approaches to women with chronic pelvic pain. Obstet Gynecol. 1991;77:740-744.

2. Jones KD, Sutton C. Patient satisfaction and changes in pain scores after ablative laparoscopic surgery for stage III–IV endometriosis and endometriotic cysts. Fertil Steril. 2003;79:1086-1090.

3. Sutton CJG, Ewen SP, Whitelaw N, Haines P. Prospective, randomized, double-blind controlled trial of laser laparoscopy in the treatment of pelvic pain associated with minimal, mild and moderate endometriosis. Fertil Steril. 1994;62:696-700.

4. Peters AAW, Trimbos-Kemper GCM, Admiral C, Trimbos JB. A randomized clinical trial on the benefit of adhesiolysis in patients with intraperitoneal adhesions and chronic pelvic pain. Br J Obstet Gynaecol. 1992;99:59-62.

5. Swank DJ, Swank-Bordewijk SC, Hop WC, et al. Laparoscopic adhesiolysis in patients with chronic abdominal pain: a blinded randomized controlled multi-centre trial. Lancet. 2003;361:1247-1251.

MEDICAL THERAPYLetrozole for endometriosis?

The discovery that endometriosis implants may contain the aromatase enzyme prompted consideration of aromatase inhibitors as a nonsurgical treatment for endometriosis. These agents, which prevent conversion of androgens to estrogens, are used in the management of breast cancer.

This pilot study evaluated the use of the aromatase inhibitor letrozole in 10 women in whom medical and surgical therapy for endometriosis had failed. Addback therapy with norethindrone acetate was given to prevent the decrease in bone mineral density that might have occurred with letrozole alone. In 9 of the 10 women, pain decreased over the 6 months of the study.

This encouraging result suggests that larger trials with control subjects and longer follow-up will be worthwhile.

Recommendation: Use GnRH agonist

Nasir L, Bope ET. Management of pelvic pain from dysmenorrhea or endometriosis. J Am Board Fam Pract. 2004;17:S43–S47.

Recommendations from the Family Practice Pain Education Project published at the end of 2004 support use of nonsurgical therapies for endometriosis, based in part on the findings of Ling et al,¹ which demonstrated the effectiveness of empirical therapy.

ACOG agrees

That recommendation is similar to the nonsurgical approach to chronic pelvic pain recommended in 1999 in an ACOG Practice Bulletin²:

“Therapy with a GnRH agonist is an appropriate approach to the management of women with chronic pelvic pain, even in the absence of surgical confirmation of endometriosis, provided that a detailed initial evaluation fails to demonstrate some other cause of pelvic pain.”

The author is a speaker and consultant for TAP Pharmaceuticals.

Here’s a disturbing fact: If it looks like HELLP syndrome, and impairs the patient like HELLP syndrome, it isn’t necessarily HELLP syndrome. A plethora of diagnostic criteria from different investigators over the years has confused the issue of what constitutes this syndrome—not to mention how to manage it.

A management issue has also attracted recent attention: use of corticosteroids either antepartum to enhance maternal status so that epidural anesthesia can be administered, or postpartum to improve platelets. Such improvements are only transient, however, and we lack definitive data on the benefits.

One thing is certain, however. The combination of hemolysis, liver dysfunction or injury, and platelet consumption in women with preeclampsia makes adverse maternal and perinatal outcomes more likely and leaves no room for expectant management.

HELLP syndrome also has become a major issue in litigation against obstetricians and medical and surgical consultants. Lawsuits usually allege misdiagnosed preeclampsia, delayed delivery, or improper recognition and management of complications.

Pinning HELLP Down

One of the best tools to identify HELLP syndrome is a healthy dose of suspicion, since it can affect any pregnant woman at any time: antepartum, intrapartum, or within 1 week postpartum. Approximately 72% of cases are diagnosed before delivery, and the rest are diagnosed during the first week postpartum.

Weinstein noted that the signs and symptoms of HELLP syndrome can occur without clinical evidence of severe preeclampsia (severe hypertension and/or severe proteinuria). Indeed, he reported that hypertension can be mild or absent in most patients with HELLP, and proteinuria can be mild.

Weinstein coined the term HELLP syndrome in 1982 to describe these abnormalities in women with preeclampsia:

• H = hemolysis
• EL = elevated liver enzymes
• LP = low platelets

Another obstacle to early detection: Patients may have nonspecific signs and symptoms, none of which are diagnostic of classical preeclampsia.

However, HELLP syndrome is most common in women who have already been diagnosed with gestational hypertension and/or preeclampsia.

HELLP is more likely with severe hypertension

Overall, the incidence of HELLP syndrome in women with gestational hypertension/preeclampsia increases with the severity of the condition. HELLP syndrome also is more likely in women with early-onset hypertension/preeclampsia (before 34 weeks’ gestation).

Making The Diagnosis

HELLP syndrome is diagnosed when all 3 of the following are present:

• Hemolysis, defined as the presence of microangiopathic hemolytic anemia. This is the hallmark of the triad.
• Elevated liver enzymes (either aspartate aminotransferase [AST] or alanine aminotransferase [ALT]). This component signifies liver cell ischemia and/or necrosis.
• Low platelet count (<100,000/mm³). TABLE 1 summarizes the laboratory criteria for the diagnosis.

When to begin testing

In women with new-onset hypertension, order a complete blood count with platelets and liver enzyme analysis at the time of diagnosis and serially thereafter. The frequency of these tests depends on the initial test results, severity of disease, and onset of symptoms.

In women without hypertension, I recommend obtaining the same blood tests at the onset of any of the signs and symptoms listed in TABLE 2.

TABLE 2

Conditions that heighten the risk of HELLP

Assessing test results

Clinicians should be familiar with the upper limit for liverenzyme tests in their laboratory. I suggest a cutoff more than twice the upper limit for a particular test.

Also keep in mind that these parameters are dynamic; some women will meet only some of the criteria early in the disease process. Moreover, maternal complications are substantially higher when all 3 components are present than when only 1 or 2 are present.

Look for these clinical findings

Hypertension. Most women with HELLP syndrome have hypertension. In 15% to 50% of cases, the hypertension is mild, but it may be absent in 15%.

Proteinuria. Most patients also have proteinuria by dipstick (≥1+). Proteinuria may be absent in approximately 13% of women with HELLP syndrome, although they will likely have many of the symptoms reported by women with severe preeclampsia.

TABLE 3 lists the signs and symptoms to be expected in these patients, along with their frequency.

TABLE 3

Signs and symptoms

The usual times of onset

Antepartum cases. As was previously noted, HELLP syndrome usually develops before delivery, with the most frequent onset being before 37 weeks’ gestation ( TABLE 4).

In the postpartum period, most cases develop within 48 hours after delivery. Of these, approximately 90% occur in women who had antepartum preeclampsia that progressed to HELLP syndrome in the postpartum period. However, approximately 20% of postpartum cases develop more than 48 hours after delivery.

Another important point: HELLP syndrome can develop for the first time postpartum in women who had no evidence of preeclampsia before or during labor. Thus, it is important to educate all postpartum women to report new symptoms (listed in TABLE 3) as soon as possible. When these symptoms develop, evaluate the patient for both preeclampsia and HELLP syndrome.

TABLE 4

Usual times of onset*

Risk for life-threatening maternal complications

When all components of HELLP syndrome are present in a woman with preeclampsia, the risk of maternal death and serious maternal morbidities increases substantially (TABLE 5). The rate of these complications depends on gestational age at onset, presence of associated obstetric complications (eclampsia, abruptio placentae, peripartum hemorrhage, or fetal demise) or preexisting conditions (lupus, renal disease, chronic hypertension, or type 1 diabetes).

Abruptio placentae increases the risk of disseminated intravascular coagulopathy (DIC), as well as the need for blood transfusions.

Marked ascites (>1 L) leads to higher rates of cardiopulmonary complications.

TABLE 5

Maternal complications

Differential diagnosis

When diagnosing HELLP syndrome, confirm or exclude the conditions listed in TABLE 6, since the presenting symptoms and clinical and laboratory findings in women with HELLP syndrome overlap those of several microangiopathic disorders that can develop during pregnancy and/or postpartum. In some women, preeclampsia may be superimposed on one of these disorders, further confounding an already difficult differential diagnosis.

Because of the remarkably similar clinical and laboratory findings of these diseases, make every effort to achieve an accurate diagnosis, since management and outcomes may differ among these conditions.

TABLE 6

Differential diagnosis

Initial Management

Hospitalize the patient

Because HELLP syndrome usually is characterized by progressive and sometimes sudden deterioration in maternal and fetal conditions, patients should be hospitalized and observed in a labor and delivery unit.

Initially, assume the patient has severe preeclampsia and treat her with intravenous magnesium sulfate to prevent convulsions and antihypertensive medications as needed to keep systolic blood pressure below 160 mm Hg and diastolic blood pressure below 105 mm Hg.

Blood tests should include:

• complete blood count with platelet count,
• peripheral smear evaluation,
• serum AST,
• lactate dehydrogenase,
• creatinine,
• bilirubin, and
• coagulation studies.

These tests help confirm the diagnosis and check for the presence of DIC, massive hemolysis, severe anemia, or renal failure.

The first priority is to assess the patient for the presence of cardiovascular complications, signs of liver hematoma or hemorrhage, and abruptio placentae. If any is present—particularly hypotension, hypovolemia, DIC, or pulmonary edema—make every effort to stabilize the maternal condition.

Can delivery wait 48 hours for corticosteroids?

Evaluate fetal status by heart rate monitoring or biophysical profile, and confirm gestational age. Then decide whether delivery is indicated or can be delayed for 48 hours so that corticosteroids can be given.

No room for expectant management. Do not consider expectant management in women with true HELLP syndrome. Delivery can only be delayed for a maximum of 48 hours—and only when both mother and fetus are stable, at 24 to 34 weeks’ gestation, and awaiting the benefit of corticosteroids.

Corticosteroid dosing. My practice is to give 2 doses of either betamethasone 12 mg intramuscularly every 12 hours or dexamethasone 12 mg intravenously every 12 hours. This is to improve maternal status, at least temporarily.

Initiate delivery within 24 hours after the last steroid dose, with continuous monitoring in the labor and delivery unit.

Although some women may demonstrate transient improvement in their blood tests (eg, increased platelet count or decreased AST levels), delivery is still indicated. Conversely, in some cases, maternal and fetal conditions may deteriorate, mandating delivery before the 2 doses of steroids are completed.

Delivery Considerations

HELLP syndrome does not justify immediate cesarean

Patients with HELLP syndrome in labor or with rupture of membranes can deliver vaginally in the absence of obstetric complications. In addition, induction or augmentation of labor is acceptable with either oxytocin infusion or prostaglandins if the fetal gestational age is 32 weeks or more and the cervical Bishop score exceeds 5.

TABLE 7 lists the indications for elective cesarean delivery and summarizes management during surgery. It is important to stabilize the maternal condition, correct coagulopathy, and have blood or blood products available before initiating surgery.

TABLE 7

Cesarean delivery: Indications and management

Watch for oozing from surgical sites

In a cesarean section, generalized oozing from the surgical site can occur during the operation or immediately postpartum because of the continued drop in platelet count in some of these patients. Thus, it is advisable to insert a subfascial drain and to leave the skin incision open for at least 48 hours to avoid hematoma formation in these areas (FIGURE 1).

FIGURE 1 Insert subfascial drain at cesarean section

Because generalized oozing from the surgical site can occur intraoperatively or immediately postpartum, insert a subfascial drain and leave the skin incision open for at least 48 hours to avoid hematoma formation.

Small doses of systemic opioids are best

For maternal analgesia during labor, give small, intermittent doses of systemic opioids. For repair of episiotomy or vulvar or vaginal lacerations, use local infiltration anesthesia.

Avoid pudendal block because of the potential for bleeding and hematoma formation in this area. Epidural anesthesia may be used after consultation with the anesthesiologist if the platelet count exceeds 75,000/mm³.

Some authors report rising platelet counts after intravenous dexamethasone and, with the improved platelets, greater use of epidural anesthesia, especially in women who achieved a 24-hour latency period before delivery. However, since the platelet count may drop again, insert the epidural catheter once the desired platelet level (with anesthesiologist approval) is reached.

Suspected Liver Hematoma

A rare and potentially life-threatening complication of HELLP syndrome is subcapsular liver hematoma (FIGURE 2). Unfortunately, the rarity of this complication sometimes causes it to be overlooked.

FIGURE 2 Rare but life-threatening: Subcapsular liver hematoma

Liver hematomas can develop antepartum, intrapartum, or postpartum. Presenting symptoms may include severe epigastric or retrosternal pain in association with respiratory difficulty (pain on inspiration), with or without shoulder or neck pain.

Early signs and symptoms

Liver hematomas can develop antepartum, during labor, or in the postpartum period. Presenting symptoms may include severe epigastric or retrosternal pain in association with breathing difficulty (pain on inspiration), with or without shoulder or neck pain.

When profound hypovolemic shock occurs in a previously hypertensive patient, suspect rupture of a liver hematoma. Diagnosis can be made by ultrasound or computed tomography (CT) imaging of the liver, both of which can also confirm intraperitoneal bleeding.

In most cases, rupture involves the right lobe of the liver and is preceded by a parenchymal liver hematoma.

Mortality can exceed 50%

Maternal and fetal mortality increase substantially when a subcapsular liver hematoma is present. In fact, mortality may exceed 50% when frank rupture of the capsule involves liver tissue.

Choose conservative management whenever possible

Management of subcapsular liver hematoma depends on maternal hemodynamic status, integrity of the capsule (ruptured or intact), and the fetal condition.

Conservative management is preferable in hemodynamically stable women with an unruptured hematoma. It consists of close monitoring of the patient’s hemodynamic and coagulation status and serial assessment of the hematoma with ultrasound or CT scan.

Avoid exogenous trauma to the liver, such as frequent abdominal palpation, emesis, or convulsions. Any sudden increase in intraabdominal pressure can led to rupture of the hematoma.

When rupture occurs

This surgical emergency requires an acute multidisciplinary team, including an Ob/Gyn, anesthesiologist, highly qualified surgeon, and a representative of the hospital’s blood bank.

Maternal resuscitation should include:

• transfusion of packed red blood cells to maintain blood pressure and tissue perfusion,
• correction of coagulopathy with fresh frozen plasma and platelets, and
• laparotomy, preferably using a cell saver.

Options at laparotomy include:

• packing and drainage (preferred),
• ligation of the hepatic lacerations,
• embolization of the hepatic artery to the affected liver segment, and
• loosely suturing omentum or surgical mesh to the liver surface.

Postpartum Care

In women who develop HELLP prior to delivery, closely monitor postpartum vital signs, intake and output, and symptoms in intensive care or a similar facility for at least 48 hours.

During this time, my practice is to give the patient intravenous magnesium sulfate and antihypertensive medications as needed to keep systolic blood pressure below 155 mm Hg (the standard is 160 mm Hg) and diastolic blood pressure below 105 mm Hg.

The rationale for this treatment is to prevent bleeding in the brain if the woman has thrombocytopenia.

When HELLP appears in the postpartum period

Several maternal complications from HELLP syndrome may not appear until immediately postpartum. Thus, all women with preeclampsia require close monitoring of vital signs, fluid intake and output, laboratory values, and pulse oximetry for at least 48 hours.

Also continue magnesium sulfate in the postpartum period and keep maternal blood pressure below 155 mm Hg systolic and 105 mm Hg diastolic.

Time to recovery

Most patients begin to improve or completely recover within 72 hours, while others deteriorate further or fail to recover for as long as 1 week after delivery. Thus, some women may require intensive monitoring for several days because of the risk of pulmonary edema, renal failure, or adult respiratory distress syndrome.

Keep in mind that, in some of these women, the cause of the postpartum deterioration may be something other than HELLP syndrome(TABLE 6).

Watch for sudden hypotension

A sudden drop in blood pressure to hypotensive levels can be an early sign of severe hemolysis or unrecognized intraperitoneal blood loss (from surgical sites or ruptured liver hematoma), as well as sepsis.

In a woman with severe hemoconcentration (ie, severe vasoconstriction), sudden hypotension also may indicate excessive vasodilation from antihypertensive drugs such as hydralazine or nifedipine, resulting in relative hypovolemia.

Such a case requires volume resuscitation, blood transfusion (if indicated), and evaluation for unrecognized bleeding.

Use of steroids

Some authors recommend giving intravenous dexamethasone (5 to 10 mg every 12 hours) for approximately 48 hours after delivery in women who develop antepartum or postpartum HELLP. They claim this treatment improves maternal blood tests, shortens recovery, and reduces maternal morbidity.

However, at present, no data indicate this approach has clinical benefit—and the risks are unknown. For these reasons, treatment with intravenous dexamethasone after delivery remains empiric.

The author reports no financial relationships relevant to this article.

Here’s a disturbing fact: If it looks like HELLP syndrome, and impairs the patient like HELLP syndrome, it isn’t necessarily HELLP syndrome. A plethora of diagnostic criteria from different investigators over the years has confused the issue of what constitutes this syndrome—not to mention how to manage it.

A management issue has also attracted recent attention: use of corticosteroids either antepartum to enhance maternal status so that epidural anesthesia can be administered, or postpartum to improve platelets. Such improvements are only transient, however, and we lack definitive data on the benefits.

One thing is certain, however. The combination of hemolysis, liver dysfunction or injury, and platelet consumption in women with preeclampsia makes adverse maternal and perinatal outcomes more likely and leaves no room for expectant management.

HELLP syndrome also has become a major issue in litigation against obstetricians and medical and surgical consultants. Lawsuits usually allege misdiagnosed preeclampsia, delayed delivery, or improper recognition and management of complications.

Pinning HELLP Down

One of the best tools to identify HELLP syndrome is a healthy dose of suspicion, since it can affect any pregnant woman at any time: antepartum, intrapartum, or within 1 week postpartum. Approximately 72% of cases are diagnosed before delivery, and the rest are diagnosed during the first week postpartum.

Weinstein noted that the signs and symptoms of HELLP syndrome can occur without clinical evidence of severe preeclampsia (severe hypertension and/or severe proteinuria). Indeed, he reported that hypertension can be mild or absent in most patients with HELLP, and proteinuria can be mild.

Weinstein coined the term HELLP syndrome in 1982 to describe these abnormalities in women with preeclampsia:

• H = hemolysis
• EL = elevated liver enzymes
• LP = low platelets

Another obstacle to early detection: Patients may have nonspecific signs and symptoms, none of which are diagnostic of classical preeclampsia.

However, HELLP syndrome is most common in women who have already been diagnosed with gestational hypertension and/or preeclampsia.

HELLP is more likely with severe hypertension

Overall, the incidence of HELLP syndrome in women with gestational hypertension/preeclampsia increases with the severity of the condition. HELLP syndrome also is more likely in women with early-onset hypertension/preeclampsia (before 34 weeks’ gestation).

Making The Diagnosis

HELLP syndrome is diagnosed when all 3 of the following are present:

• Hemolysis, defined as the presence of microangiopathic hemolytic anemia. This is the hallmark of the triad.
• Elevated liver enzymes (either aspartate aminotransferase [AST] or alanine aminotransferase [ALT]). This component signifies liver cell ischemia and/or necrosis.
• Low platelet count (<100,000/mm³). TABLE 1 summarizes the laboratory criteria for the diagnosis.

When to begin testing

In women with new-onset hypertension, order a complete blood count with platelets and liver enzyme analysis at the time of diagnosis and serially thereafter. The frequency of these tests depends on the initial test results, severity of disease, and onset of symptoms.

In women without hypertension, I recommend obtaining the same blood tests at the onset of any of the signs and symptoms listed in TABLE 2.

TABLE 2

Conditions that heighten the risk of HELLP

Assessing test results

Clinicians should be familiar with the upper limit for liverenzyme tests in their laboratory. I suggest a cutoff more than twice the upper limit for a particular test.

Also keep in mind that these parameters are dynamic; some women will meet only some of the criteria early in the disease process. Moreover, maternal complications are substantially higher when all 3 components are present than when only 1 or 2 are present.

Look for these clinical findings

Hypertension. Most women with HELLP syndrome have hypertension. In 15% to 50% of cases, the hypertension is mild, but it may be absent in 15%.

Proteinuria. Most patients also have proteinuria by dipstick (≥1+). Proteinuria may be absent in approximately 13% of women with HELLP syndrome, although they will likely have many of the symptoms reported by women with severe preeclampsia.

TABLE 3 lists the signs and symptoms to be expected in these patients, along with their frequency.

TABLE 3

Signs and symptoms

The usual times of onset

Antepartum cases. As was previously noted, HELLP syndrome usually develops before delivery, with the most frequent onset being before 37 weeks’ gestation ( TABLE 4).

In the postpartum period, most cases develop within 48 hours after delivery. Of these, approximately 90% occur in women who had antepartum preeclampsia that progressed to HELLP syndrome in the postpartum period. However, approximately 20% of postpartum cases develop more than 48 hours after delivery.

Another important point: HELLP syndrome can develop for the first time postpartum in women who had no evidence of preeclampsia before or during labor. Thus, it is important to educate all postpartum women to report new symptoms (listed in TABLE 3) as soon as possible. When these symptoms develop, evaluate the patient for both preeclampsia and HELLP syndrome.

TABLE 4

Usual times of onset*

Risk for life-threatening maternal complications

When all components of HELLP syndrome are present in a woman with preeclampsia, the risk of maternal death and serious maternal morbidities increases substantially (TABLE 5). The rate of these complications depends on gestational age at onset, presence of associated obstetric complications (eclampsia, abruptio placentae, peripartum hemorrhage, or fetal demise) or preexisting conditions (lupus, renal disease, chronic hypertension, or type 1 diabetes).

Abruptio placentae increases the risk of disseminated intravascular coagulopathy (DIC), as well as the need for blood transfusions.

Marked ascites (>1 L) leads to higher rates of cardiopulmonary complications.

TABLE 5

Maternal complications