Ischemic heart disease is the leading cause of death in the U.S., accounting for approximately 490,000 deaths in 1993. ¹ The American Heart Association estimates that approximately 1.5 million Americans will suffer a myocardial infarction (MI) in 1995, and one third will not survive the event. ² Atherosclerotic coronary artery disease (CAD) is the underlying cause of most ischemic cardiac events and can result in myocardial infarction, congestive heart failure, cardiac arrhythmias, and sudden cardiac death. Clinically significant CAD is uncommon in men under 40 and premenopausal women, but risk increases with advancing age and in the presence of risk factors such as smoking, hypertension, diabetes, high cholesterol, and family history of heart disease. Although mortality from heart disease has declined steadily over the past three decades in the U.S., ² the total burden of coronary disease is predicted to increase substantially over the next 30 years due to the increasing size of the elderly population. ³ The cost of medical care and lost economic productivity due to heart disease in the U.S. has been projected to exceed $60 billion in 1995. ²

Angina is the most common presenting symptom of myocardial ischemia and underlying CAD, but in many persons the first evidence of CAD may be myocardial infarction or sudden death. ⁴ It has been estimated that 1-2 million middle-aged men have asymptomatic but physiologically significant coronary disease, also referred to as silent myocardial ischemia. ^4,5

There are two screening strategies to reduce morbidity and mortality from CAD. The first involves screening for modifiable cardiac risk factors, such as hypertension, elevated serum cholesterol, cigarette smoking, physical inactivity, and diet (see Chapters 2,3, and 54-56). The second strategy is early detection of asymptomatic CAD. The principal tests for detecting asymptomatic CAD include resting and exercise ECGs, which can provide evidence of previous silent myocardial infarctions and silent or inducible myocardial ischemia. Thallium-201 scintigraphy, exercise echocardiography, and ambulatory ECG (Holter monitoring) are less commonly used for screening purposes. The efficacy of each of these tests may be evaluated by (a) its ability to detect atherosclerotic plaque, and (b) its ability to predict the occurrence of a serious clinical event in the future (acute MI, sudden cardiac death).

Several resting ECG findings (ST depression, T-wave inversion, Q waves, and left axis deviation) increase the likelihood of coronary atherosclerosis and of future coronary events. However, these findings are uncommon in asymptomatic persons, occurring in only 1-4% of middle-aged men without clinical evidence of CAD, ^6,7 and they are not specific for CAD. One third to one half of patients with angiographically normal coronary arteries have Q waves, T-wave inversion, or ST-T changes on their resting ECG. ^8-10 Conversely, a normal ECG does not rule out CAD. In the Coronary Artery Surgery Study, 29% of patients with symptomatic, angiographically proven CAD demonstrated a normal resting ECG. ¹¹ Asymptomatic persons with baseline ECG abnormalities (Q waves, ST segment depression, T-wave inversion, left ventricular hypertrophy, and ventricular premature beats) have a higher risk of future coronary events. ^6,12-19 However, prospective studies lasting between 5 and 30 years have found that symptomatic CAD develops in only 3-15% of persons with these ECG findings. ^6,13,18,20 Furthermore, most coronary events occur in persons without resting ECG abnormalities. ^6,7,18,21,22 Thus, routine ECG testing in asymptomatic persons, in whom the pretest probability of having CAD is relatively low, is not an efficient process for detecting CAD or for predicting future coronary events.

The exercise ECG is more accurate than the resting ECG for detecting clinically important CAD. Most patients with asymptomatic CAD do not have a positive exercise ECG, however. ^23-26 ECG changes often do not become apparent until an atherosclerotic plaque has progressed to the point that it significantly impedes coronary blood flow. ^24,27 In addition, most asymptomatic persons with an abnormal exercise ECG result (usually defined by a specific magnitude of ST-segment depression) do not have underlying CAD. ^27,28 A 1989 meta-analysis found considerable variability in the accuracy of exercise-induced ST depression for predicting CAD (sensitivity 23-100%, specificity 17-100%). ²⁹ Although several investigators reported that adjusting the ST segment for heart rate (ST/HR slope or ST/HR index) improves the ability to predict significant CAD ^30-32 and future coronary events, ²⁵ other studies have not shown an advantage. ^33-37

The exercise ECG is also more accurate than the resting ECG in predicting future coronary events. While asymptomatic persons with a positive exercise ECG are more likely to experience an event than those with negative tests, ^25,38-43 longitudinal studies following such patients from 4 to 13 years have shown that only 1-11% will suffer an acute MI or sudden death. ^25,42,44,45 As with resting ECG, the majority of events will occur in those with a negative exercise test result. ^24,26,44-47 The pathophysiology of acute coronary syndromes may explain the insensitivity of exercise ECG for subsequent coronary events. Unstable angina, MI, and sudden death often result from an acute, occluding thrombus precipitated by the rupture of a mild, non-flow-limiting plaque. ^48-50 Among healthy men who subsequently developed symptomatic CAD after a negative screening test, 73% experienced a MI or sudden death as their initial manifestation. ^24,45 In contrast, the majority of asymptomatic persons with a positive exercise ECG develop angina as their initial event. ^5,24,45,51 Thus, while exercise ECG may predict the presence of more severe coronary stenosis and risk of angina in asymptomatic persons, it does not accurately predict risk of acute coronary events.

The addition of thallium-201 scintigraphy to conventional exercise testing improves its accuracy in detecting CAD, making it a useful diagnostic test in persons with symptoms of CAD. ^52,53 However, the probability of CAD after a positive scan is low in asymptomatic persons, and most coronary events occur in those with a negative test result. ^23,44 Because of these limitations and its expense, thallium-201 scintigraphy is not a practical screening test for asymptomatic persons. ^23,44,52,54 The ambulatory ECG can detect episodes of ST-segment depression which may indicate silent ischemia in asymptomatic persons with CAD. These episodes, however, also occur commonly in healthy volunteers ^55-57 and are not reliable predictors of future coronary events, even in asymptomatic or mildly symptomatic patients with documented CAD. ^58,59 There have been no studies of exercise echocardiography in screening asymptomatic populations for CAD.

False-positive screening test results are undesirable for several reasons. Persons with abnormal results frequently undergo invasive diagnostic procedures such as coronary angiography. Abnormal test results may produce considerable anxiety. An abnormal ECG tracing may disqualify some patients from jobs, insurance eligibility, and other opportunities, although the extent of these problems is not known. Proposed strategies for reducing false-positive results include: performing workups in accordance with a Bayesian model ⁶⁰ using discriminant functions to interpret the stress ECG ⁴¹ and targeting testing to high-risk groups.

Although case-control and cohort studies show that asymptomatic persons with selected ECG findings are at increased risk of MI and cardiac death, ^{5,7,22,25,38-43} there is little evidence that routine screening is an effective means to reduce the incidence of acute coronary events in asymptomatic persons. Antianginal drugs such as nitroglycerin, beta -adrenergic blockers, and calcium channel blockers reduce the frequency and the duration of silent ischemia. ^61-63 In a recent study, atenolol reduced the incidence of cardiac events (MI, cardiac arrest, or worsening angina) in patients who had both silent ischemia and CAD documented by angiography or prior MI ^64,65 extrapolating these benefits to completely asymptomatic patients with silent ischemia on routine screening may not be justified, given their much lower risk of acute events. ⁴⁶

Both aspirin therapy and drug treatment for high cholesterol reduce the incidence of MI and cardiac mortality in patients with symptomatic coronary disease, but the balance of risks and benefits of these therapies in asymptomatic patients is not resolved (see Chapters 2 and 69). Benefits are more likely to exceed risks in asymptomatic patients with underlying coronary disease, however, due to their higher absolute risk of MI and coronary death. New diagnostic techniques may prove more sensitive than angiography in identifying the mild-to-moderate plaques that are a risk factor for developing an acute occlusive thrombus. ^66,67 Their utility will remain in question, however, until appropriate trials demonstrate that early detection and treatment of small coronary plaques is more effective than treatment based on identifiable risk factors (e.g., high blood pressure or high cholesterol) in asymptomatic patients. ^48,49

Among patients with symptomatic coronary disease, coronary artery bypass grafting prolongs life compared with medical therapy in patients with left main coronary or three-vessel disease with poor left ventricular function. ¹¹ The prevalence of high-risk coronary disease among asymptomatic persons, however, is very low while some patients may suffer a MI or sudden cardiac death as their initial manifestation of CAD, most patients with severe coronary disease initially develop angina. ^5,45 As a result, it is not clear that the benefit of identifying a small number of individuals with severe coronary disease before they develop symptoms is sufficient to justify routine screening of large populations of asymptomatic persons. Recent randomized trials have demonstrated that percutaneous transluminal coronary angioplasty (PTCA) reduces the frequency of angina in patients with symptomatic CAD, but it does not reduce the incidence of MI or cardiac death. ^68,69 The value of coronary angioplasty for asymptomatic coronary stenoses is not known.

A screening ECG has been recommended to provide a "baseline" to help interpret changes in subsequent ECGs. ⁷⁰ Even when important differences are noted between the baseline ECG and a subsequent tracing, these do not necessarily reflect ongoing or recent ischemia. Using the development of a new Q wave on serial ECG as a criterion, the Framingham Study reported an annual incidence of unrecognized MI of 5.4/1,000 men aged 65-74. ⁷¹ Less specific changes develop more commonly than Q waves. Baseline ECGs are often not available when needed for comparison, nor do they significantly contribute to decision making for patients being evaluated for chest pain, ^72-75 especially in those with no history of cardiovascular disease. ⁷⁶ One large study found that a baseline ECG was available in 55% of patients evaluated for acute chest pain. ⁷³ The availability of a prior ECG was associated with small but significant reduction in hospitalization rates for those patients who had chest pain not due to acute MI. Only a small subset of the asymptomatic population is likely to benefit from having a baseline ECG, however: those with baseline ECG abnormalities suggestive of ischemia who subsequently develop acute noncardiac chest pain. Savings from preventing a few unnecessary hospitalizations among these patients must be weighed against the high costs of routine ECG screening in the large population of asymptomatic persons.

Another argument for ECG screening is that the early identification of persons at increased risk for CAD on the basis of ECG findings may help to modify other important cardiac risk factors such as cigarette smoking, hypertension, and elevated serum cholesterol. ⁷⁰ While the efficacy of risk factor modification is well established, ^22,77 no studies have evaluated whether identifying high-risk patients with abnormal ECGs improves efforts to modify risk factors or leads to better clinical outcomes.

Periodic ECG screening is often recommended for persons who might endanger public safety were they to experience an acute cardiac event at work (e.g., airline pilots, bus and truck drivers, railroad engineers). Cardiac events in such individuals are more likely to affect the safety of a large number of persons, and clinical intervention, either through medical treatment or work restrictions, might prevent such catastrophes. No studies have addressed the efficacy of ECG screening in these persons, however.

Preliminary exercise ECG testing has also been recommended for sedentary persons planning to begin vigorous exercise programs, based on evidence that strenuous exertion may increase the risk of sudden cardiac death. The usual underlying cause of sudden cardiac death during exercise is hypertrophic cardiomyopathy or congenital coronary anomalies in young persons and CAD in older persons. Cardiac events during exercise in persons without symptomatic heart disease are uncommon, however, and exercise ECG may not accurately predict those who are at risk. Among over 3,600 asymptomatic, hypercholesterolemic middle-aged men who underwent submaximal exercise ECG during the Lipid Research Clinics Coronary Primary Prevention Trial, 62 (2%) subsequently experienced an acute cardiac event during moderate or strenuous physical activity during follow-up (average 7.4 years). ⁷⁸ Although men with exercise-induced ECG changes were at increased risk, only 11 of 62 events occurred in men with an abnormal baseline exercise test (sensitivity 18%). Moreover, few of the men with abnormal test results experienced an activity-related event during follow-up (positive predictive value 4%). Although the negative predictive value of baseline ECG was high (over 98%), it was no better than multivariate analysis based on clinical risk factors alone. Given the low incidence of activity-related events in middle-aged men, and the uncertain benefit of restricting activity in those with abnormal exercise tests, the potential benefits of pre-exercise testing appear small. In populations at low risk for heart disease, any benefits of detecting the rare individual with asymptomatic CAD may be offset by adverse effects of labeling and exercise restrictions for the larger number of persons with false-positive ECG results.

The routine use of resting electrocardiogram to screen for CAD in asymptomatic adults is not recommended by the American College of Physicians (ACP) ⁷⁹ or the Canadian Task Force on the Periodic Health Examination. ⁸⁰ The American Academy of Family Physicians (AAFP) recommends a baseline electrocardiogram for men 40 years and older with two or more cardiac risk factors and sedentary men about to begin a vigorous exercise program this recommendation is under review. ⁸¹ A task force sponsored by the American College of Cardiology and the American Heart Association (ACC/AHA) recommends baseline testing for all persons over 40 years of age and for those about to have exercise stress testing. ⁸²

The AAFP recommends exercise electrocardiography for those whose jobs are linked to public safety (e.g., pilots, air traffic controllers) or that require high cardiovascular performance (e.g., police officers, firefighters). ⁸¹ The American College of Sports Medicine recommends exercise ECG testing for men over age 40, women over age 50, and other asymptomatic persons with multiple cardiac risk factors, prior to beginning a vigorous exercise program. ⁸³ The ACC/AHA recognize that the exercise ECG is frequently used to screen asymptomatic persons in some high-risk groups but concluded that there is divergence of opinion with respect to its usefulness. ⁸⁴ The ACP does not recommend exercise testing with ECG or thallium scintigraphy as a routine screening procedure in asymptomatic adults. ^79,85

Heart disease is the leading cause of death in the U.S., and interventions that produce even modest reductions in the incidence of acute ischemic events may have substantial public health benefits. Although the resting electrocardiogram can detect evidence of coronary heart disease in asymptomatic persons and identify individuals at increased risk of future coronary events, the ECG has important weaknesses as a screening test. The large majority of asymptomatic persons with abnormal ECG results do not have CAD and are at relatively low risk for developing symptomatic heart disease in the near future. Routine screening may subject many of them to the inconvenience, expense and potential risks of follow-up testing (i.e., cardiac catheterization or radionuclide imaging) to evaluate false-positive screening results. Although exercise testing is more sensitive and specific for high-grade coronary stenoses, the exercise ECG is too time-consuming and expensive for routine use in asymptomatic persons. Finally, neither resting nor exercise ECG reliably detects the mild to moderate atherosclerotic lesions which are often responsible for acute coronary events.

A second important problem with screening for asymptomatic CAD is the lack of evidence that earlier detection leads to better outcomes. The only interventions proven to reduce coronary events in asymptomatic persons are modifications of risk factors such as smoking, high cholesterol, and elevated blood pressure. These interventions, however, should be encouraged for all patients with modifiable risk factors, not only those with screening tests suggestive of CAD. The benefits of more invasive treatments for coronary stenosis (e.g., bypass surgery, angioplasty) are unproven in asymptomatic persons. For certain occupations, such as pilots and heavy equipment operators, where sudden death or incapacitation would endanger the safety of others, considerations other than benefit to the individual patient may favor screening. Although screening cannot reliably identify all persons at risk of an acute event, it may increase the margin of safety for the public.

To minimize the potential adverse effects of false-positive test results, routine screening with ECG should be avoided in populations where the prevalence of CAD is low, including most adults under 40, and middle-aged men and women without coronary risk factors. Even in high-risk individuals, the benefits of screening to identify asymptomatic CAD are unproven. For some persons, however, identifying those at high risk of coronary mortality may help guide treatment decisions (e.g., use of aspirin or cholesterol-lowering drugs).

There are major costs associated with widespread screening with resting ECG in asymptomatic adults, and use of other screening tests (ambulatory ECG, exercise testing, and echocardiography) would be substantially more expensive. ⁷⁹ The inconvenience, expense, and potential risks of routine screening might be justified if it significantly reduced the incidence of MI and sudden cardiac death, but such evidence is not yet available. Until appropriate studies demonstrate a benefit of screening for CAD, identification and treatment of major cardiac risk factors such as hypertension, elevated serum cholesterol, and cigarette smoking remain the only proven measures for reducing coronary morbidity and mortality in asymptomatic persons.

CLINICAL INTERVENTION

There is insufficient evidence to recommend for or against screening middle-aged and older men and women for asymptomatic coronary artery disease with resting electrocardiography (ECG), ambulatory ECG, or exercise ECG ("C" recommendation). Recommendations against routine screening may be made on other grounds for persons who are not at high risk of developing symptomatic CAD these grounds include the limited sensitivity and low predictive value of an abnormal resting ECG in asymptomatic persons, and the high costs of screening and follow-up. Screening selected high-risk asymptomatic persons (e.g., those with multiple cardiac risk factors) is indicated only where results will influence treatment decisions (e.g., use of aspirin or lipid-lowering drugs in asymptomatic persons). Screening individuals in certain occupations (pilots, truck drivers, etc.) can be recommended on other grounds, including possible benefits to public safety. The choice of specific screening test for asymptomatic CAD is left to clinical discretion: exercise ECG is more accurate than resting ECG but is considerably more expensive.

Routine ECG screening as part of the periodic health visit or preparticipation sports physical is not recommended for asymptomatic children, adolescents, and young adults ("D" recommendation).

Clinicians should emphasize proven measures for the primary prevention of coronary disease in all patients (see Chapter 3, Screening for Hypertension Chapter 2, Screening for High Blood Cholesterol Chapter 54, Counseling to Prevent Tobacco Use Chapter 55, Counseling to Promote Physical Activity and Chapter 56, Counseling to Promote a Healthy Diet).

The draft update of this chapter was prepared for the U.S. Preventive Services Task Force by Dennis L. Disch, MD, and Harold C. Sox, Jr., MD.

Elevated blood cholesterol is one of the major modifiable risk factors for coronary heart disease (CHD), ¹ the leading cause of death in the U.S. CHD accounts for approximately 490,000 deaths each year, ² and angina and nonfatal myocardial infarction (MI) are a source of substantial morbidity. CHD is projected to cost over $60 billion in 1995 in the U.S. in medical expenses and lost productivity. ³ The incidence of CHD is low in men under age 35 and in premenopausal women (1-2/1,000 annually), ⁴ but climbs exponentially during middle age for both men and women. The onset of CHD is delayed approximately 10 years in women compared with men, probably due to effects of estrogen, ⁵ but women account for 49% of all CHD deaths in the U.S. ² Clinical events are the result of a multifactorial process that begins years before the onset of symptoms. Autopsy studies detected early lesions of atherosclerosis in many adolescents and young adults. ^6-10 The onset of atherosclerosis and symptomatic CHD is earlier among persons with inherited lipid disorders such as familial hypercholesterolemia (FH) ¹¹ and familial combined hyperlipidemia (FCH). ¹²

Epidemiologic, patho-logic, animal, genetic, and clinical studies support a causal relationship between blood lipids (usually measured as serum levels) and coronary atherosclerosis. ^1,13-15 Extended follow-up of large cohorts (predominantly middle-aged men) ^16-18 provides evidence that CHD risk increases in a continuous and graded fashion, beginning with cholesterol levels as low as 150-180 mg/dL [a] this association extends to cholesterol levels measured as early as age 20 in men. ^14,19 During middle age, for each 1% increase in total cholesterol, CHD risk increases by an estimated 3%. ²⁰ High cholesterol (>=240 mg/dL) is also a risk factor in middle-aged women, but most coronary events in women occur well after menopause. ^5,17,21-24 Some studies report that cholesterol alone is a weak predictor of CHD mortality in the elderly, ^24a,190 but an overview of 24 cohort studies indicates that high cholesterol remains a risk factor for CHD after age 65, ²³ with the strongest associations among healthier elderly populations followed over longer periods. ^25-27 The association is weaker in older women than in men ²³ and is not consistent for cholesterol levels measured after age 75. ^28-31

Expert panels have defined high and "borderline high" (200-239 mg/dL) cholesterol to simplify clinical decisions. ¹ Because CHD is a multifactorial process, however, there is no definition of high cholesterol that discriminates well between individuals who will or will not develop CHD. ^32,33 Due to nonlipid risk factors, persons with cholesterol below 240 mg/dL account for the majority of all CHD events. ^34,35 Among middle-aged men, 9-12% of those with cholesterol 240 mg/dL or greater will develop symptomatic CHD over the next 7-9 years, ^34,36 but most of them have multiple other risk factors for CHD. ³⁵ The excess (i.e., absolute) risk due to high cholesterol (and the probable benefit of lowering cholesterol) increases with the underlying risk of CHD. In a 12-year study of over 316,000 men aged 35-57, the excess CHD mortality attributable to high cholesterol was greatest in men over age 45, and in those who smoked or had hypertension. ¹⁶ The increase in CHD mortality associated with a given increment in serum cholesterol was steepest at very high values (>300 mg/dL). ¹⁶ Excess risk from high cholesterol is smaller in women, who have less than half the CHD risk as do men at any given cholesterol level. ^17,23,37 Although the relative risk associated with high serum cholesterol declines with age, ^17,23,28 the excess risk generally does not, due to the much higher incidence of CHD in older persons. ^31,38,39

The risk associated with high total cholesterol is primarily due to high levels of low-density lipoprotein cholesterol (LDL-C), ¹ but there is a strong, independent, and inverse association between high-density lipoprotein cholesterol (HDL-C) levels and CHD risk. ^40-42 Low HDL-C increases risk even when cholesterol is below 200 mg/dL, ⁴¹ a pattern present in up to 20% of men with confirmed CHD. ⁴³ In many studies, measures of HDL-C or the ratio of total cholesterol to HDL-C are better predictors of CHD risk than is serum cholesterol alone. ^{5,22,23,24a,41,44} High total cholesterol in association with high HDL-C (>=60 mg/dL) is common in older women (especially those taking estrogen) but is not associated with an increased risk for CHD. ^1,41 The importance of triglycerides as an independent risk factor for CHD remains uncertain. ^40,45 Three large studies reported strong associations between triglyceride levels over 200-300 mg/dL (2.26-3.39 mmol/L) and cardiovascular mortality in women, ^21,22,24 but other analyses found no association after controlling for obesity, fasting glucose, or low HDL-C. ⁴⁶ The combination of high triglycerides and low HDL-C often occurs in association with other CHD risk factors such as hypertension and diabetes and is associated with a high risk of CHD. ^46a

Serum total cholesterol and LDL-C increase 1-2 mg/dL per year in men from ages 20-40, 2 mg/dL per year in women from ages 40-60, ⁴⁷ and an average 18% during the perimenopausal period, due in part to age-related increases in weight. ⁴⁸ The prevalence of serum cholesterol 240 mg/dL or higher increases from 8-9% in adults under age 35 to nearly 25% for men age 55 and nearly 40% for women over 65. ⁴⁹ Approximately 11% of men and 3% of women over age 20 have low HDL-C (<35 mg/dL) with desirable or borderline-high total cholesterol. ⁴⁹

Both total cholesterol and HDL-C can be measured in venipuncture or finger-stick specimens from fasting or nonfasting individuals. Due to normal physiologic variation and measurement error, a single measurement may not reflect the patient's true (or average) cholesterol level. Stress, minor illness, posture, and seasonal fluctuations may cause serum cholesterol to vary 4-11% within an individual. ⁵⁰ Laboratory assays are subject to random errors, due to variation in sample collection, handling, and reagents, and to systematic errors (bias), due to methods that consistently overestimate or underestimate cholesterol values. ⁵¹ In a survey of 5,000 clinical laboratories, 93% of the measurements were within 9% of a reference standard. ⁵² Desktop analyzers can produce reliable results, but some devices may not meet standards for accuracy. ⁵³ Variation in training and operating technique can introduce additional error when instruments are used outside clinical laboratories. ⁵⁴ Average bias for measurements based on capillary specimens compared to venous specimens was +4-7%. ⁵⁵

As a result of these considerations, a single measure of serum cholesterol could vary as much as 14% from an individual's average value under acceptable laboratory conditions. ⁵⁰ For an individual with a "true" cholesterol level of 200 mg/dL, the 95% range of expected values is 172-228 mg/dL. ⁵⁶ Some authorities therefore recommend advising patients of their "cholesterol range," rather than a single value. ⁵⁶ Where more precise estimates are necessary, an average of at least two measurements on two occasions has been recommended, and a third if the first two values differ by more than 16%. ⁵⁰

Although cholesterol levels in child-hood correlate moderately well with levels in adulthood (correlation coefficient 0.4-0.6), many children with elevated serum cholesterol (defined as serum cholesterol >=200 mg/dL or LDL-C >=130 mg/dL, the 90-95th percentile in U.S. children under 19 years) ⁵⁷ do not have high cholesterol as adults. ^58-60 Furthermore, the association between childhood cholesterol levels and CHD in adults has not been studied. Because of the familial aggregation of CHD and hypercholesterolemia, ^57,61,62 some experts recommend screening for family history of either premature cardiovascular disease (age 55 or younger) or parental hypercholesterolemia (>=240 mg/dL) to identify a subset of children who are more likely to be at risk from hypercholesterolemia as adults. ⁵⁷ Under this definition, only 25% of all children would be screened, but the predictive value of family history is limited: 81-90% of children with such histories have normal cholesterol. ^63-66 Even when parental cholesterol has been measured and found to be elevated, most children have normal cholesterol values. ^57,67,68

Parental and childhood cholesterol levels are highest in heterozygous FH (estimated prevalence 1 in 500), which is strongly associated with premature CHD. Up to 50% of men with FH develop clinical CHD by age 50. ^69,70 Screening based on family history, as defined above, does not appear to be an efficient strategy for detecting FH, however. Many children would be screened, and few of those identified and treated for high cholesterol would have FH. ⁷¹ By itself, a parental history of premature CHD is likely to detect less than half of all children with FH. ⁷⁰ Tracing and screening families of index cases with FH may be more cost-effective than population screening for FH. ⁷²

Measurements of HDL-C and triglyc-erides are less reliable than measurement of total cholesterol due to greater biologic and analytic variability. ^73,74 The 95% range of expected values for an individual with HDL-C of 37 mg/dL is 29-45 mg/dL. ⁷⁵ A survey of 250 laboratories found that one third of all HDL-C measurements varied more than 10% from a reference value. ⁷⁶ Triglycerides must be measured on fasting specimens. Even then, intraindividual variation is greater than 20%, and a single measure is inadequate to categorize levels as high or normal. ^73,74 Measurement of apolipoproteins (e.g., apoB) has been evaluated as a screening test for FH, familial coronary disease, and high LDL-C, but these assays are not yet widely available or adequately standardized. ⁵⁷

No long-term study has compared routine cholesterol screening to alternate strategies (selective case-finding or universal dietary advice without screening) with change in cholesterol levels or CHD incidence as an outcome. The increase in cholesterol screening over the past decade in the U.S. has been accompanied by significant improvements in dietary knowledge, ⁷⁷ fat consumption, ⁷⁸ average cholesterol levels, ⁷⁹ and CHD mortality, ¹⁴ but it is difficult to isolate the contribution of screening from other factors (e.g., public education, changes in food supply) that may account for these trends. In community- or practice-based trials, patients receiving risk-factor screening and targeted dietary advice had slightly lower average cholesterol levels (1-3%) than did unscreened controls at 1-3-year follow-up, but dietary interventions were limited. ^80-82 Whether screening improves the effectiveness of routine dietary advice has been examined in two short-term studies where all subjects received counseling about diet cholesterol screening modestly improved mean cholesterol levels in one study but had no effect in the other. ^83,84 In a school-based study in which all children received similar health education, cardiovascular risk-factor screening (including cholesterol measurement) was associated with improved dietary knowledge and self-reported behavior, but changes in lipid levels were not assessed. ⁸⁵

The primary evidence to support cholesterol screening is the ability of cholesterol-lowering interventions to reduce the risk of CHD in patients with high cholesterol. These benefits are now well established for persons with preexisting atherosclerotic vascular disease. In individual trials and overviews of studies enrolling persons with angina or prior myocardial infarction (MI), cholesterol-lowering treatments slowed the progression of atherosclerosis, ⁸⁶ reduced the incidence of CHD, ^87,88 and reduced overall mortality. ⁸⁹ In the first long-term trial of newer cholesterol-lowering drugs, treatment with simvastatin over 5.4 years reduced coronary mortality 42% and all-cause mortality 30% in 4,444 men and women with coronary disease. ⁹⁰

The absolute benefit of treating high cholesterol in persons without cardiovascular disease, however, is much smaller due to the much lower risk of death or MI (annual CHD mortality 0.1-0.3% in middle-aged men with asymptomatic high cholesterol vs. 2-10% per year in patients with symptomatic CHD). ⁹¹ The risks and benefits of lowering cholesterol in asymptomatic persons -- primarily middle-aged men with very high cholesterol -- have been examined in trials using medications, modified diets in institutional patients, or outpatient dietary counseling, and in overviews of these trials.

Three large, multicenter, placebo-controlled trials of lipid-lowering medications provide the best evidence that lowering cholesterol can reduce combined CHD incidence (fatal and nonfatal events) in asymptomatic persons. These trials enrolled hypercholesterolemic middle-aged men (age 30-59, mean cholesterol 246-289 mg/dL) and lowered total cholesterol 9-10% (and LDL-C 10-13%) over periods of 5-7 years. In the World Health Organization Cooperative Trial, treatment with clofibrate significantly reduced the incidence of nonfatal MI by 25%, ⁹² but this benefit was offset by significant increases in noncardiac and total mortality (40% and 30% respectively, p = 0.01). ⁹³ The Lipid Research Clinics (LRC) Coronary Primary Prevention Trial reported a significant 19% reduction in cumulative incidence of MI and sudden cardiac death in patients treated with cholestyramine over 7 years (7.0% vs. 8.6%). ³⁶ In the Helsinki Heart Study, treatment with gemfibrozil significantly reduced the 5-year cumulative incidence of cardiac events by 34% (2.7% vs. 4.1%). ⁹⁴ Most of the benefit of gemfibrozil was confined to men with a high ratio of LDL-C to HDL-C (>=5) and triglycerides >200 mg/dL. ⁹⁵ Effects on CHD mortality were not statistically significant in any of these trials. Two additional drug trials reported 1-3-year results in largely asymptomatic populations. ^96,97 Roughly 30% of subjects had CHD at entry, however, and these patients accounted for most of the coronary events during follow-up.

Demonstrating a clinical benefit of modern cholesterol-lowering diets in asymptomatic persons has proven difficult. In three controlled trials in institutionalized patients, fat-modified diets reduced serum cholesterol 12-14% with generally favorable effects on CHD over periods of up to 8 years. ^98-100 Each of these studies used diets high in polyunsaturated fat, which have been associated with adverse effects, ¹⁵ and none excluded patients with CHD. As a result, their findings may not be applicable to currently recommended low-fat diets in asymptomatic persons.

The only trials to examine the clinical benefits of a diet low in total and saturated fat in persons without CHD are multifactorial intervention trials, which offered dietary counseling, smoking cessation advice, and/or treatment of high blood pressure to middle-aged men. ^101-105 Among Norwegian smokers with very high cholesterol levels (mean 320 mg/dL) and fat consumption (44% calories), dietary advice lowered cholesterol 13% and, in conjunction with smoking cessation, reduced CHD incidence by 47%. ¹⁰³ The remaining trials achieved much smaller (0-5%) reductions in cholesterol and insignificant effects on CHD the benefits of intervention in some studies may have been limited by ineffective counseling and follow-up, ^101,104 lower cholesterol levels at baseline, ¹⁰¹ or adverse effects of other therapies. ^102,105 In the most systematic test of dietary counseling in adults, 10 weekly group sessions and periodic individual counseling were provided over 6 years to over 6,000 men (mean cholesterol 253 mg/dL). ¹⁰² Average cholesterol level declined 5% in men receiving counseling, but only 2% compared to controls. Greater changes were observed in men who lost at least 5 pounds and those with higher serum cholesterol at baseline, ¹⁰⁶ but there was no significant reduction in CHD mortality or incidence in the intervention group. ^102,107

Short-term metabolic studies and selected trials in patients with CHD indicate that reducing dietary saturated fat and/or increasing polyunsaturated fat intake can reduce elevated total and LDL-C as much as 10-20%. ^108-110 Due to variable compliance, trials of diet counseling in the primary care setting have achieved much smaller and inconsistent average reductions in serum cholesterol in asymptomatic persons (0-4%). ^{80-82,111-116} Although larger changes have been reported in uncontrolled follow-up studies after cholesterol screening, ^117,118 these results may be biased by selective or short-term follow-up and regression to the mean in persons with high cholesterol. Ongoing studies are examining the efficacy of cholesterol screening and intervention in primary care settings in the U.S. ¹¹⁹ More stringent diets can produce larger reductions in cholesterol, ¹²⁰ but long-term data in asymptomatic persons are limited. Two trials in women at risk for breast cancer lowered total fat intake to 20% of calories and reduced total cholesterol 6-7% over 1-2 years. ^121,122

At least 10 quantitative overviews (meta-analyses) of randomized trials have attempted to resolve uncertainties about the risks and benefits of lowering cholesterol, including effects on mortality. ^{18,88,89,91,123-128} Three recent overviews provide the most comprehensive analyses of long-term cholesterol-lowering trials published through 1993 35 diet and drug trials were included in one analysis, ⁹¹ 28 in the second (excluding trials that used estrogens or thyroxine), ^18,89 and 22 in the third (all trials achieving at least a 4% reduction in cholesterol for at least 3 years). ¹²⁸ These overviews support a dose-response relationship between change in serum cholesterol and reduction in CHD incidence (fatal and nonfatal events combined) comparable to that predicted from epidemiologic studies: after 2-5 years of treatment, each 1% reduction in serum cholesterol yields a 2-3% reduction in total CHD, for both diet and drug interventions, and in patients with or without CHD at entry. ^18,89,128

When only trials enrolling asymptomatic persons were analyzed, however, neither CHD mortality nor total mortality was significantly reduced by cholesterol lowering: ¹²⁸ difference in total mortality among treated versus control subjects = +6%, 95% confidence interval (CI) -3% to +17%. ⁸⁹ Moreover, noncardiac mortality was increased 20-24% among patients treated with lipid-lowering medications. ^89,91,128 While observing similar effects of treatment, each overview offered distinct interpretations of these findings. Law et al. concluded that the increase in noncoronary mortality was most likely due to chance: the finding was of borderline statistical significance (p = 0.02), did not reflect any consistent cause of excess mortality among trials, and was independent of compliance with therapy. ⁸⁹ Gordon attributed adverse effects to trials employing hormones or fibrate medications. ¹²⁸ Davey Smith et al. concluded that lipid-lowering drugs reduced overall mortality in high-risk persons (i.e., persons with CHD), but were harmful in those at lower risk. ⁹¹ When trials were stratified by the observed CHD mortality in the control group, drug treatment was associated with a significant 20% increase in all-cause mortality in 10 trials enrolling low-risk subjects (CHD mortality <1% per year), including the WHO, LRC, and Helsinki studies. ⁹¹ A single trial (the WHO clofibrate study) accounts for nearly half of all patient-years of treatment in persons without CHD ¹²⁸ and has a strong influence on results of any meta-analysis.

Due to methodologic concerns about combining results from trials employing different cholesterol-lowering drugs and diets, meta-analysis cannot prove or disprove possible harms from lipid-lowering medications. ¹²⁹ These analyses, however, illustrate the importance of underlying CHD risk in determining whether expected benefits are likely to justify possible risks of treatment. Even if drugs are safe, the margin of benefit may be small for many persons with asymptomatic hypercholesterolemia. In the LRC and Helsinki trials, preventing one coronary death required treating 300-400 middle-aged men for 5-7 years. ^36,94 The benefits of lipid-lowering medications on nonfatal CHD are more pronounced but must be weighed against the unpleasant and occasionally serious side effects of some drugs (see below). ^92,127,130 The newest class of lipid-lowering drugs, HMG-CoA reductase inhibitors or "statins," lowers cholesterol more effectively and appears to be well-tolerated in trials lasting up to 6 years. ^90,97 These drugs are more likely to have significant effects on mortality in patients without CHD, but long-term trials of these agents in asymptomatic persons have yet to report results. ¹³¹

Lipid-lowering medications and diet effectively lower cholesterol in women, ¹³² but no trial has specifically examined the benefits of cholesterol reduction in asymptomatic women. ¹³³ Trials that included female subjects with CHD observed qualitatively similar benefits of cholesterol reduction on angiographic or clinical endpoints in women and men. ^90,99,133 In the 4S trial, simvastatin significantly reduced CHD incidence, but not mortality, in women with CHD. ⁹⁰ Two trials in women without CHD, with a cumulative enrollment of more than 6,000 women, observed no effect of drug or diet treatment on CHD incidence or mortality after 1-3 years ^96,100 the short duration of follow-up may have limited the power of these studies to detect a difference. ¹³³ Long-term data on drug therapy in women are limited, with the exception of estrogen therapy (see Chapter 68).

The benefit of lowering cholesterol in older persons has been questioned due to the weak association between serum cholesterol and all-cause mortality after age 60. ^17,28,30 Associations between cholesterol and mortality in unselected elderly populations, however, are likely to be confounded by the increasing prevalence of chronic illnesses which increase mortality and independently lower serum cholesterol. ^26,134,135 Direct evidence that cholesterol reduction is beneficial in asymptomatic older persons is not yet available, but cholesterol-lowering diets and medications reduced overall mortality 26-30% in persons over 60 with clinical CHD. ^90,136,137 In two trials in patients without CHD that included older subjects, however, cholesterol reduction produced significant benefits in younger but not in older patients (over age 60 or 65). ^96,98 Newer cholesterol-lowering agents are efficacious and well-tolerated in older patients. ^90,138 A large multicenter trial is under way to examine the effectiveness of pravastatin and various antihypertensive medications in asymptomatic persons over age 60 with hypertension and high cholesterol. ¹³⁸ There are few controlled trials of dietary counseling to lower cholesterol in older patients no significant change in cholesterol levels was observed among rural Medicare recipients offered diet counseling ¹³⁹ or older patients receiving diet counseling and placebo medication. ¹³⁸

Determining the benefits of lowering cholesterol in children, adolescents, and young adults is difficult, due to their low near-term risk of clinical coronary disease. The assumption that early treatment is more effective than treatment begun later in life ⁵⁷ rests on observations that early atherosclerosis is present in many adolescents and young adults, is associated with lipid levels, progresses with age, ⁶ and is difficult to reverse in middle age. ⁸⁶ New evidence, however, suggests that much of the clinical benefit of lowering cholesterol can be achieved within 2-5 years of initiating therapy. ¹⁸ These benefits have been attributed to stabilizing "lipid-rich" lesions ⁸⁷ and improving endothelial function, ¹⁴⁰ and they suggest that the additional benefits of early drug therapy for hypercholesterolemia (i.e., before middle age) may not justify the added expense and possible risks of longer treatment. Intensive diet or drug intervention for adolescents and young adults with FH, although never tested in a prospective trial, has become standard treatment due to the very high levels of LDL-C and dramatically increased risk of premature CHD in persons with FH. ^11,71 Even in FH, however, most clinical events occur in middle age (i.e., after age 40), and risk is variable: MI was rare before age 30 in men in one study, and onset of CHD is later in women and nonsmokers with FH. ^69,141

Modified diets lower cholesterol in young adults, but the contribution of universal screening in motivating risk reduction in young persons is uncertain. Neither a multiple-intervention trial in Australian workers ¹⁴² nor a study of risk assessment in a general practice in the U.K. ¹¹⁶ demonstrated that screening and dietary advice led to long-term reduction in cholesterol levels in younger men (under age 35-40). The effectiveness of screening and dietary counseling has not been adequately studied in young adults and cannot be predicted reliably from studies in middle-aged men.

Dietary fat intake in children is associated with total cholesterol and LDL-C levels, ^143,144 but controlled trials have not consistently demonstrated that individual dietary counseling is effective in children. ^145-147 Results from the largest trial reported that children with elevated LDL-C who received intensive family-oriented dietary counseling (30 sessions over 3 years) experienced a significant but modest (3.2 mg/dL) reduction in mean LDL-C compared with controls. ¹⁴⁸ Uncontrolled studies of dietician counseling for hyperlipidemic children and adolescents have reported larger short-term reductions in mean cholesterol and LDL-C, ^149-153 but such studies are prone to bias from regression to the mean and selective follow-up. Physical activity and fitness are associated with higher levels of HDL-C in children and adolescents, but controlled and uncontrolled trials ^154-159 have reported inconsistent effects of exercise interventions on lipids. Drug therapy effectively lowers cholesterol in children, but side effects limit compliance with bile-acid resins, the only therapy currently recommended for routine use in children. ⁵⁷ In one study of 80 children with FH or FCH, only 13% were still compliant with resin therapy after 3 years. ¹⁶⁰ Ongoing studies are examining the safety and efficacy of newer agents in children.

Measurement of serum cholesterol is safe and relatively inexpensive, but widespread screening may have some undesirable consequences. In populations in which the potential benefits of early detection may be small (e.g., low-risk young persons), the possibility of harm may influence decisions about universal screening. ¹⁶¹ Anecdotal reports have reported decreased well-being in persons diagnosed with high cholesterol (i.e., "labeling"), ¹⁶² but a prospective study did not confirm this effect. ¹⁶³ Other possible adverse effects of screening include inconvenience and expense of screening and follow-up, opportunity costs to the busy clinician, misinformation due to inaccurate results, and reduced attention to diet in persons with "desirable" cholesterol levels. ¹⁶⁴ The importance of possible adverse effects of screening has not been systematically studied.

The safety of cholesterol-lowering interventions is especially important in children and young persons. Dietary restrictions may reduce intake of calories, calcium, vitamins, and iron in children, ^165-167 and failure-to-thrive due to excessively fat-restricted diets has been reported, albeit rarely, in children. ^168,169 In the most comprehensive trial of dietary intervention in children, however, no adverse effects on growth, sexual development, psychological measures, iron status, or blood micronutrients were detected at 3-year follow-up. ¹⁴⁸ Other controlled studies also support the safety of properly performed dietary intervention in children. ^147,166,170 The elderly may also be at risk from modified diets if adequate intake of calories, calcium, and essential vitamins is not maintained, but these effects have not been directly examined.

The inappropriate use of drug therapy is of greater concern, especially in young persons in whom the benefit of early drug treatment may not justify the costs and possible risks. ^18,161 According to a national survey of pediatricians and family physicians, one in six regularly prescribed drugs for hypercholesterolemic children, and a substantial number did so based on inappropriate criteria, or used drugs not routinely recommended for children. ¹⁷¹ Persons under age 40 accounted for over 1 million prescriptions for lipid-lowering drugs in 1992 ¹⁷² gemfibrozil was the second most commonly prescribed lipid-lowering drug in the U.S. in 1992, ¹⁷² despite limited indications for its use ¹ and important safety concerns. Fibrate medications (e.g., clofibrate and gemfibrozil) have been associated with an increase in gallstone disease, ⁹² adverse trends in CHD mortality ^93,173 and cancer mortality in individual trials, ^93,174 and a significant increase in noncoronary mortality in a recent overview of long-term trials. ¹²⁸ HMG-CoA reductase inhibitors have not been associated with important adverse effects in trials lasting up to 6 years. ⁹⁰ The safety of lifelong therapy with these agents cannot yet be determined several medications in this class have been reported to cause liver tumors in animal studies.

The importance of detecting low HDL-C or high triglycerides remains unproven, especially in persons with normal serum cholesterol. Weight loss in obese subjects, ^132,175 smoking cessation, exercise, ^176,176a and moderate alcohol consumption ¹⁷⁷ can raise HDL-C and/or lower triglyceride levels. Some of these lifestyle interventions have only small effects, however, and most can be recommended independent of lipid levels. Most importantly, no trial has directly examined the benefit of raising HDL-C or lowering triglycerides. ^40,45 Secondary analyses of several trials have attributed varying proportions of the clinical benefit of drug therapy to increases in HDL-C, ^40,94,95 or reductions in triglycerides, ¹³⁶ but all of the subjects had high total or LDL cholesterol. The benefit of drug treatment for low HDL-C and normal cholesterol has not been determined but is being studied in men with CHD. ⁴³

The National Cholesterol Education Program Adult Treatment Panel II, convened by the National Heart, Lung, and Blood Institute, recommends routine measurement of nonfasting total cholesterol and HDL-C in all adults age 20 or older at least once every 5 years. ^1,178 The Canadian Task Force on the Periodic Health Examination concluded there was insufficient evidence to recommend routine cholesterol screening but endorsed case-finding in men 30-59 years old. ¹²⁷ The American Academy of Family Physicians ¹⁷⁹ recommends measurement of total cholesterol at least every 5 years in adults age 19 and older these recommendations are under review. The American College of Obstetricians and Gynecologists recommends periodic screening of cholesterol in all women over age 20, and in selected high-risk adolescents. ¹⁸⁰ In guidelines revised in 1995, the American College of Physicians (ACP) concluded that screening serum cholesterol was appropriate but not mandatory for asymptomatic men aged 35-65 and women aged 45-65 screening is not recommended for younger persons unless they are suspected of having a familial lipoprotein disorder or have multiple cardiac risk factors. The ACP concluded that evidence was not sufficient to recommend for or against screening asymptomatic persons between the ages of 65 and 75, but it recommends against screening after age 75. ¹⁸¹

Selective screening of children and adolescents is recommended by the National Cholesterol Education Program Expert Panel on Blood Cholesterol Levels in Children and Adolescents, ⁵⁷ the American Academy of Pediatrics (AAP), ¹⁸² the Bright Futures guidelines, ¹⁸³ the American Medical Association Guidelines for Adolescent and Preventive Services (GAPS), ¹⁸⁴ and the American Academy of Family Physicians. ¹⁷⁹ Screening with nonfasting cholesterol in all children and adolescents who have a parental history of hypercholesterolemia, and with fasting lipid profile in those with a family history of premature cardiovascular disease, is recommended. These organizations recommend that children who have multiple risk factors for CHD (such as smoking or obesity) and whose family history cannot be ascertained be screened at the discretion of the physician.

Elevated serum cholesterol is an important risk factor for CHD in men and women in the U.S., and there is now good evidence that lowering serum cholesterol can reduce the risk of CHD. Whereas measures that lower serum cholesterol and provide other health benefits (e.g., regular physical activity, reducing dietary fat, and maintaining a healthy weight) should be encouraged in all persons, cholesterol screening can identify high-risk individuals who are most likely to benefit from individualized dietary counseling or drug treatment. In addition, screening may help clinicians and patients identify priorities for risk factor modification and reinforce public awareness of the importance of a healthy diet.

Some important questions remain, however, about routine lipid screening in asymptomatic and low-risk persons, including when to begin screening and which constituents to measure. Overall, evidence is strongest for screening for high serum cholesterol in middle-aged men (ages 35-65), based on the reduction in coronary morbidity in trials enrolling asymptomatic men with very high cholesterol (mean 280 mg/dL). The epidemiology and pathophysiology of CHD is similar in men and women, suggesting that reducing high cholesterol levels will also reduce CHD in asymptomatic women. Extrapolations to premenopausal women may not be appropriate, given their low risk of CHD and the apparent protective effects of estrogen on CHD incidence. The optimal age to screen women is not known the later onset of hypercholesterolemia and CHD suggests that routine screening should begin around age 45.

Direct evidence that screening and intervention is effective in persons over age 65 is not yet available, but epidemiologic studies indicate that the risks of high cholesterol extend up to age 75. Given the high risk of CHD in the elderly, and the benefits of lowering cholesterol in symptomatic older men and women, screening may be reasonable in older persons who do not have major comorbid illnesses. Since individual cholesterol levels usually plateau by age 65 in women (and earlier in men), continued screening is less important in patients who have had desirable cholesterol levels throughout middle age.

There is not yet evidence that routine lipid screening is effective in reducing cholesterol levels or CHD risk in younger populations. Universal screening is an inefficient way to identify the small number of hypercholesterolemic young persons at risk for premature CHD, most of whom have multiple nonlipid risk factors or a history suggestive of familial dyslipidemia. Most "high-risk" young persons (excluding young men with FH) have a near-term risk of CHD well below that of hypercholesterolemic middle-aged men, ¹⁸⁵ and are not appropriate candidates for early drug therapy. Screening young persons can provide information to help stimulate lifestyle changes, but promoting a healthy lifestyle (e.g., healthy diet, regular physical activity, etc.) is important for all young persons, including the majority with "desirable" cholesterol levels. International comparisons suggest that cholesterol levels explain only part of the strong association between diet and heart disease. ^186a As a result, it is uncertain whether routine cholesterol screening in low-risk younger populations is of sufficient benefit to justify the inconvenience, costs, and possible risks of screening and treatment. In a study modeling benefits of cholesterol screening, a conservative strategy of screening only middle-aged men and others with multiple CHD risk factors produced benefits comparable to screening all adults over age 20 if interventions had adverse effects on quality of life, the more conservative strategy was preferable. ¹⁸⁶ Should future studies demonstrate that routine screening and targeted interventions are more effective in the primary care setting than universal dietary advice in young persons, this would provide some additional justification for early screening.

The benefits of screening children are even less certain. Progression of atherosclerosis in childhood is limited, many children with high cholesterol are not hypercholesterolemic as adults, and it is uncertain whether or not reducing cholesterol levels in childhood will significantly alter the risk of CHD many years later. Given the limited effectiveness of dietary counseling, poor compliance with currently recommended drug therapy, and the potential for adverse reactions in children, widespread pediatric screening might result in more harm than good.

The benefit of measuring HDL-C or triglycerides at initial screening is unproven. Measures to lower high triglycerides or raise HDL-C (e.g., weight reduction in obese persons and exercise) have relatively modest effects and should be encouraged regardless of lipid levels. Measures of HDL-C and lipoprotein analysis improve the estimation of coronary risk and should be obtained to guide treatment decisions in patients with high total cholesterol. There is, however, no evidence that they significantly improve the management of patients who do not have high total cholesterol.

While a single cholesterol test is relatively inexpensive, the cumulative costs of screening can be substantial under protocols calling for measurement of HDL-C, periodic screening, and detailed evaluation and treatment of the large population with high cholesterol. To be effective, dietary interventions require regular follow-up and reinforcement. Under optimistic assumptions, tailored dietary therapy in middle-aged men is estimated to cost more than $20,000 per year of life gained, when costs of screening and follow-up are included. ¹⁸⁷ Drug treatment of asymptomatic middle-aged men (assuming no important adverse effects) has been estimated to cost at least $50,000-90,000 per year of life saved. ^35,188 HMG-CoA reductase inhibitors are substantially more expensive than earlier medications, but they lower LDL-C more effectively and also raise HDL-C. These agents may improve the cost-effectiveness of drug therapy for asymptomatic hypercholesterolemia, especially in high-risk men, ¹⁸⁹ but the long-term safety and effectiveness of these agents in persons without CHD have not yet been established.

CLINICAL INTERVENTION

Periodic screening for high blood cholesterol, using specimens obtained from fasting or nonfasting individuals, is recommended for all men ages 35-65 and women ages 45-65 ("B" recommendation). There is insufficient evidence to recommend for or against routine screening in asymptomatic persons after age 65, but screening may be considered on a case-by-case basis ("C" recommendation). Older persons with major CHD risk factors (smoking, hypertension, diabetes) who are otherwise healthy may be more likely to benefit from screening, based on their high risk of CHD and the proven benefits of lowering cholesterol in older persons with symptomatic CHD. Cholesterol levels are not a reliable predictor of risk after age 75, however. There is insufficient evidence to recommend routine screening in children, adolescents, or young adults ("C" recommendation). For adolescents and young adults who have a family history of very high cholesterol, premature CHD in a first-degree relative (before age 50 in men or age 60 in women), or major risk factors for CHD screening may be recommended on other grounds: the greater absolute risk attributable to high cholesterol in such persons, and the potential long-term benefits of early lifestyle interventions in young persons with high cholesterol. Recommendations against routine screening in children may be made on other grounds, including the costs and inconvenience of screening and follow-up, greater potential for adverse effects of treatment, and the uncertain long-term benefits of small reductions in childhood cholesterol levels.

The appropriate interval for periodic screening is not known. Periodic screening is most important when cholesterol levels are increasing (e.g., middle-aged men, perimenopausal women, and persons who have gained weight). An interval of 5 years has been recommended by experts, ¹ but longer intervals may be reasonable in low-risk subjects (including those with previously desirable cholesterol levels).

There is insufficient evidence to recommend for or against routine measurement of HDL-C or triglycerides at initial screening ("C" recommendation). For high-risk persons (middle-aged persons with high cholesterol or multiple nonlipid risk factors for CHD), measurement of HDL-C or lipoprotein analysis can be recommended to help identify individuals at highest risk of CHD, in whom individual diet or drug therapy may be indicated.

Decisions about interventions for high cholesterol should be based on at least two measures of cholesterol and assessment of the absolute risk of CHD in each individual. This assessment should take into account the age of the patient (higher risk in men over 45 and women over 55), results of lipoprotein analysis (or ratio of total cholesterol to HDL-C), and the presence and severity of other risk factors for CHD (see above). ¹⁷⁸ More specific algorithms for risk assessment have been published. ¹⁸⁵ Initial therapy for patients with elevated cholesterol is counseling to reduce consumption of fat (especially saturated fat) and promote weight loss in overweight persons. A two-step dietary program effective in lowering serum cholesterol has been described in detail elsewhere. ¹ Benefits of drug therapy are likely to justify costs and potential risks only in persons at high risk of CHD (e.g., middle-aged men and postmenopausal women with very high cholesterol or multiple risk factors). The risks and benefits of drug therapy in asymptomatic persons over 65 have not yet been determined. In postmenopausal women with high cholesterol, estrogen therapy can lower LDL-C and raise HDL-C and is associated with lower risk of CHD in epidemiologic studies (see Chapter 68). Patients should receive information on the potential benefits, costs, and risks of long-term therapy before beginning treatment on cholesterol-lowering drugs.

All adults, adolescents, and children over age 2 years, including those with normal cholesterol levels, should receive periodic counseling regarding dietary intake of fat and saturated fat (see Chapter 56) and other measures to reduce the risk of coronary disease (see Chapters 3, 54, and 55).

The draft update of this chapter was prepared for the U.S. Preventive Services Task Force by David Atkins, MD, MPH, and Carolyn DiGuiseppi, MD, MPH.

Hypertension is usually defined as a diastolic blood pressure of 90 mm Hg or higher or a systolic pressure of 140 mm Hg or higher. ¹ It is present in an estimated 43 million Americans and is more common in blacks and older adults. ^1a Hypertension is a leading risk factor for coronary heart disease, congestive heart failure, stroke, ruptured aortic aneurysm, renal disease, and retinopathy. These complications of hypertension are among the most common and serious diseases in the U.S., and successful efforts to lower blood pressure could thus have substantial impact on population morbidity and mortality. Heart disease is the leading cause of death in the U.S., accounting for nearly 740,000 deaths each year (287 deaths per 100,000 population), and cerebrovascular disease, the third leading cause of death, accounts for about 150,000 deaths each year (58/100,000). ² Milder forms of hypertension predict progression to more severe elevations and development of cardiovascular disease. ^1,3,4 Coronary heart disease mortality begins to increase at systolic blood pressures above 110 mm Hg and at diastolic pressures above 70 mm Hg. ⁵ The prevalence of unrecognized and uncontrolled hypertension, and the mortality from cardiovascular disease, have declined substantially in the U.S. in the past several decades. ¹

Treatable (also known as secondary) causes of hypertension such as aortic coarctation or renovascular disease also may be associated with severe consequences, including congestive heart failure, aortic rupture, or stroke. ^6-9 There are no population data available for estimating the true prevalence of secondary hypertension. The incidence of coarctation of the aorta has been estimated at 0.2-0.6/1,000 live births and the prevalence at 0.1-0.5/1,000 children. ^10-12

The most accurate devices for measuring blood pressure (e.g., intra-arterial catheters) are not appropriate for routine screening because of their invasiveness, technical limitations, and cost. Office sphygmomanometry (the blood pressure cuff) remains the most appropriate screening test for hypertension in the asymptomatic population. Although this test is highly accurate when performed correctly, false-positive and false-negative results (i.e., recording a blood pressure that is not representative of the patient's average blood pressure) do occur in clinical practice. ¹³ One study found that 21% of persons diagnosed as mildly hypertensive based on office sphygmomanometry had no evidence of hypertension when 24-hour ambulatory recordings were obtained. ¹⁴

Errors in measuring blood pressure may result from instrument, observer, and/or patient factors. ¹⁵ Examples of instrument error include manometer dysfunction, pressure leaks, stethoscope defects, and cuffs of incorrect width or length for the patient's arm size. The observer can introduce errors due to sensory impairment (difficulty hearing Korotkoff sounds or reading the manometer), inattention, inconsistency in recording Korotkoff sounds (e.g., Phase IV vs. Phase V), and subconscious bias (e.g., "digit preference" for numbers ending with zero or preconceived notions of "normal" pressures). The patient can be the source of misleading readings due to posture and biologic factors. Posture (i.e., lying, standing, sitting) and arm position in relation to the heart can affect results by as much as 10 mm Hg. ¹⁵ Biologic factors include anxiety, meals, tobacco, alcohol, temperature changes, exertion, and pain. Due to these limitations in the test-retest reliability of blood pressure measurement, it is commonly recommended that hypertension be diagnosed only after more than one elevated reading is obtained on each of three separate visits over a period of one to several weeks. ¹

Additional factors affect accuracy when performing sphygmomanometry on children these difficulties are especially common when testing infants and toddlers under 3 years of age. ^16-18 First, there is increased variation in arm circumference, requiring greater care in the selection of cuff sizes. ¹⁹ Second, the examination is more frequently complicated by the anxiety and restlessness of the patient. Third, the disappearance of Korotkoff sounds (Phase V) is often difficult to hear in children and Phase IV values are often substituted. Fourth, erroneous Korotkoff sounds can be produced inadvertently by the pressure of the stethoscope diaphragm against the antecubital fossa. Finally, the definition of pediatric hypertension has itself been uncertain because of confusion over normal values during childhood. The definition of hypertension in childhood is essentially arbitrary, based on age-specific percentile. ¹⁸ Age-, sex-, and height-specific blood pressure nomograms for U.S. children and adolescents have been published more recently, based on data from 56,108 children aged 1-17 years. ²⁰

Self-measured (home) blood pressure and ambulatory blood pressure monitoring may provide useful information in special circumstances (e.g., research, persistent "white-coat" hypertension), but there is insufficient evidence at present to warrant their routine use in screening. ^1,21-28

There is a direct relationship between the magnitude of blood pressure elevation and the benefit of lowering pressure. In persons with malignant hypertension, the benefits of intervention are most dramatic treatment increases 5-year survival from near zero (data from historical controls) to 75%. ²⁹ Over the past 30 years, the results of many randomized clinical trials of the effects of antihypertensive drug therapy on morbidity and mortality in adult patients (>=21 years of age) with less severe hypertension have been published. ^30-32 The efficacy of treating hypertension is clear, as demonstrated in a number of older randomized controlled trials in adults with diastolic blood pressures ranging from 90 to 129 mm Hg. ^33-38 For example, in the Veterans Administration Cooperative Study on Antihypertensive Agents, middle-aged men with diastolic blood pressure averaging 90 through 114 mm Hg experienced a significant reduction in "morbid" events (e.g., cerebrovascular hemorrhage, congestive heart failure) after treatment with antihypertensive medication. ³⁴

Persons with mild (Stage 1) to moderate (Stage 2) ¹ diastolic hypertension (90-109 mm Hg) also benefit from treatment. ^30,39-41 This was confirmed in the Hypertension Detection and Follow-Up Program, a randomized controlled trial involving nearly 11,000 hypertensive men and women, of whom 40% were black. ³⁹ The intervention group received standardized pharmacologic treatment ("stepped care") while the control group was referred for community medical care. There was a statistically significant 17% reduction in 5-year all-cause mortality in the group receiving standardized drug therapy the subset with diastolic blood pressure 90-104 mm Hg experienced a 20% reduction in mortality. ³⁹ Deaths due to cerebrovascular disease, ischemic heart disease, and other causes were also significantly reduced in the stepped care group. ⁴² Similar effects on all-cause mortality and cardiovascular events have been reported in other randomized controlled trials, such as the Australian National Blood Pressure Study (initial diastolic blood pressure 95-109 mm Hg) ⁴⁰ and the Medical Research Council (MRC) trial (diastolic blood pressure 90-109 mm Hg). ⁴¹ In these two trials, the relative reduction in rates of stroke or other trial endpoints with treatment was similar in those with diastolic blood pressures <95 or 95-99 mm Hg and those with higher diastolic blood pressures, although the absolute benefit was less due to smaller initial risk of stroke and other diseases at lower blood pressures. Both trials included untreated control groups and did not report a significant reduction in deaths from noncardiovascular causes in the actively treated groups, confirming that the benefit was due to antihypertensive treatment rather than to other medical care.

Earlier studies included some subjects over age 65 years, but in insufficient numbers to permit firm conclusions. Four large, randomized placebo-controlled trials have since demonstrated conclusively the benefit of antihypertensive treatment in elderly subjects (aged 60-97 years). ^43-48 Three of these studies included persons with diastolic blood pressures of 90-120 mm Hg, and among them reported significant reductions in all-cause mortality, ⁴⁶ cardiovascular mortality, ^43,46 cardiovascular events, ⁴⁷ and strokes. ^46,47 The Systolic Hypertension in the Elderly Program (SHEP) trial included over 4,000 subjects >=60 years of age with isolated systolic hypertension (systolic blood pressure >= 160 mm Hg, with diastolic blood pressure < 90 mm Hg), and reported significant reductions in the incidence of stroke, myocardial infarction, and left ventricular failure. ⁴⁸ A meta-analysis combining these and other trials that included persons aged >=60 years demonstrated that antihypertensive treatment in elderly persons significantly reduced mortality from all causes (-12%), stroke (-36%), and coronary heart disease (-25%), as well as stroke and coronary heart disease morbidity. ⁴⁹ This meta-analysis suggested reduced benefit with increasing age, although differences were not statistically significant. A second meta-analysis of randomized controlled trials in persons over age 60 years concluded that absolute 5-year morbidity and mortality benefits derived from trials were greater for older than for younger subjects. ⁵⁰ This meta-analysis calculated that 18 (95% CI, 14-25) elderly hypertensive subjects needed to be treated for 5 years to prevent one cardiovascular event.

Treatment of hypertension is associated with multiple benefits, including reduced coronary heart disease and vascular deaths, but meta-analyses suggest it produces the largest reductions in cerebrovascular morbidity and mortality. ^30-32,49,50 Improved treatment of high blood pressure has been credited with a substantial portion of the greater than 50% reduction in age-adjusted stroke mortality that has been observed since 1972. ^1,51,52

Although the efficacy of antihypertensive treatment for essential (also called primary) hypertension has been well established in clinical research, certain factors may influence the magnitude of benefit from hypertension screening achieved in actual practice. Compliance with drug therapy may be limited by the inconvenience, side effects, and cost of these agents. ^53,54 Serious or life-threatening drug reactions in the clinical trials were rare, but less serious side effects were common, resulting in discontinuation of randomized treatment (almost 20% by the fifth year in the MRC trial, ⁴¹ for example) or a substantial increase in patient discomfort. ³⁴ Higher incidences of mild hypokalemia, hyperuricemia, and elevated fasting blood sugar have also been reported in treated individuals. ³⁵ A population-based case-control study suggested an increased risk of primary cardiac arrest with certain diuretic regimens (e.g., higher doses, use without potassium-sparing therapy). ⁵⁵ However, current drug regimens, including low-dose diuretics, are associated with fewer adverse effects and with favorable effects on quality of life. ^55a Newer classes of drugs (e.g., calcium channel blockers, angiotensin-converting enzyme inhibitors) have not been assessed in long-term trials with clinical endpoints. Their effects on cardiovascular morbidity and mortality may differ from the effects reported in the clinical trials cited above, which used diuretics or beta-blockers.

Whether hypertension screening is equally effective for other populations or with treatments other than drugs is less clear. The benefits of hypertension treatment are less well studied in certain population groups, such as children (see below), Native Americans, Asians and Pacific Islanders, and Hispanics. The effects of nonpharmacologic first-line therapy (i.e., weight reduction in overweight patients, increased physical activity, sodium restriction, and decreased alcohol intake) on cardiovascular morbidity and mortality are unstudied. Although these nonpharmacologic therapies can sometimes lower blood pressure in the short term, ^1,56-62a the magnitude of blood pressure reduction achieved is generally smaller than that achieved with drug therapy, and both the magnitude and duration of reduction in actual practice may be limited by biologic factors (e.g., varying responsiveness to sodium restriction) and the difficulties of maintaining behavioral changes (e.g., weight loss). Some of these interventions, such as sodium restriction, may also have adverse effects on quality of life. ⁶³

The detection of high blood pressure during childhood is of potential value in identifying those children who are at increased risk of primary hypertension as adults and who might benefit from earlier intervention and follow-up. Hypertensive vascular and end-organ damage may begin in childhood, ^64-69 although it is unclear how strongly these pathophysiologic changes are associated with subsequent cardiovascular disease. Prospective cohort studies have shown that children with high blood pressure are more likely than other children to have hypertension as adults. ^70-78 Correlation coefficients from these studies were generally less than 0.5, however, suggesting a limited role for high blood pressure in childhood as a predictor of adult hypertension. Although controlled trials in children show that short-term (up to 3 years) effects on blood pressure can be achieved with changes in diet and activity, ^79-82 studies demonstrating long-term changes in blood pressure are lacking. There are no trials showing that lowering blood pressure in childhood results in reduced blood pressure in adulthood. A relationship between lowering blood pressure during childhood and improved morbidity and mortality in later life is unlikely to be demonstrated, given the difficulty of performing such studies.

A relatively high proportion of children with hypertension have secondary, potentially curable forms. Among children and adolescents whose hypertension was evaluated in primary care centers, an estimated 28% had secondary hypertension (e.g., renal parenchymal disease, coarctation of the aorta). ⁶⁹ This contrasts with hypertensive adults seen in primary care settings, of whom only 7% are estimated to have secondary hypertension. ⁸³ Screening children and adolescents may be justifiable if the morbidity of these conditions is improved by early detection and treatment. Many causes of secondary hypertension in childhood are detectable by careful history-taking (e.g., preterm birth, umbilical artery catheter, chronic pyelonephritis, renal disease, bronchopulmonary dysplasia symptoms of cardiac, renal, endocrinologic, or neurologic disease) or physical examination (e.g., murmur, decreased femoral pulses, abdominal bruit). ^69,84 Characteristic symptoms and signs, such as those of aortic coarctation, are often overlooked, however. ^85-87 Numerous surgical case series suggest that delay in surgical repair of aortic coarctation increases the likelihood of irreversible hypertension, ^88-94 although none of these series controlled for other differences between persons presenting early versus late in life. Uncontrolled studies indicate that some important causes of hypertension for which definitive cures are available, including coarctation and renovascular disease, may not be diagnosed until complications such as congestive heart failure, aortic rupture, or stroke occur. ^6-9 Prognosis with early surgical intervention is improved compared with historical controls. ^88,95

Recommendations for adults have been issued by the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure, ¹ and similar recommendations have been issued by the American Heart Association. ⁹⁶ These call for routine blood pressure measurement at least once every 2 years for adults with a diastolic blood pressure below 85 mm Hg and a systolic pressure below 130 mm Hg. Measurements are recommended annually for persons with a diastolic blood pressure of 85-89 mm Hg or systolic blood pressure of 130-139 mm Hg. Persons with higher blood pressures require more frequent measurements. The American College of Physicians (ACP) ⁹⁷ and the American Academy of Family Physicians (AAFP) ⁹⁸ recommend that all adults 18 years and older be screened for hypertension every 1-2 years. The AAFP policy is currently under review. The ACP also recommends screening at every physician visit for other reasons, and that those in high-risk groups (e.g., diastolic 85-89 mm Hg, previous history of hypertension) be screened on an annual basis. The Canadian Task Force on the Periodic Health Examination recommends that all persons aged 21 years and over receive a blood pressure measurement during any visit to a physician ("case finding"). ⁹⁹

The American Academy of Pediatrics (AAP), ¹⁰⁰ the National Heart, Lung, and Blood Institute, ¹⁸ the AAFP, ⁹⁸ Bright Futures, ¹⁰¹ the American Medical Association, ¹⁰² and the American Heart Association ¹⁰³ recommend that children and adolescents receive blood pressure measurements every 1 or 2 years during regular office visits. The Canadian Task Force found insufficient evidence to recommend for or against routine blood pressure measurement in persons under age 21 years. ⁹⁹ The AAP recommends against universal neonatal blood pressure screening. ¹⁰⁴

It is clear from several large randomized clinical trials that lowering blood pressure in hypertensive adults is beneficial and that death from several common diseases can be reduced through the detection and treatment of high blood pressure. Estimates suggest that an average diastolic blood pressure reduction of 5-6 mm Hg in everyone with hypertension could reduce the incidence of coronary heart disease by 14% and the incidence of strokes by 42%. ^30,31 At the same time, it is important for clinicians to minimize the potential harmful effects of detection and treatment. For example, if performed incorrectly, sphygmomanometry can produce misleading results. Some hypertensive patients thereby escape detection (false negatives) and some normotensive persons receive inappropriate labeling (false positives), which may have certain psychological, behavioral, and even financial consequences. ¹⁰⁵ Treatment of hypertension can also be harmful as a result of medical complications, especially related to drugs. Clinicians can minimize these effects by using proper technique when performing sphygmomanometry, making appropriate use of nonpharmacologic methods, and prescribing antihypertensive drugs with careful adherence to published guidelines. ^1,106-108

The diastolic blood pressure above which therapy has been proven effective (i.e., diastolic blood pressure > 90 mm Hg) is to a large extent based on the artificial cutpoints chosen for study purposes rather than on a specific biologic cutpoint defining increased risk. The coronary heart disease mortality risk associated with blood pressure occurs on a continuum that extends well below the arbitrarily defined level for abnormal blood pressure, beginning for systolic blood pressure above 110 mm Hg and for diastolic pressure above 70 mm Hg. ⁵ Nevertheless, many organizations outside the U.S. have been reluctant to recommend drug therapy for persons with diastolic blood pressures below 100 mm Hg who lack additional risk factors. ^106,108-111 Drug treatment of mild hypertension is of particular concern for young adults: the evidence for therapeutic benefit comes primarily from several older trials ^34,36,38 that included only a few individuals in their 20s, the potential adverse effects of decades of antihypertensive therapy are undefined, and the absolute benefits in young adults are likely to be limited given their small risk of stroke and coronary heart disease. For persons with mild hypertension, most recommendations suggest including age and/or the presence of other cardiovascular disease risk factors or concomitant diseases (e.g., smoking, obesity, renal disease, peripheral vascular disease) to modify treatment decisions. ^{1,106,108-111}

Tracking studies and pathophysiologic evidence suggest there may be some benefit from early detection of primary hypertension in childhood, but there is insufficient evidence to support routine screening solely for this purpose. The lack of evidence is of concern because it is unclear whether a policy of routinely screening all children and adolescents to detect primary hypertension would achieve sufficient clinical benefit later in life to justify the costs and potential adverse effects of widespread testing and treatment. Potentially curable causes of hypertension, which account for a relatively large proportion of cases in young children, are often overlooked on history and physical examination, with rare but potentially catastrophic consequences. Evidence from case series and multiple time series indicate that early detection of secondary hypertension in childhood is of substantial benefit to the small number of patients affected.

CLINICAL INTERVENTION

Periodic screening for hypertension is recommended for all persons >=21 years of age ("A" recommendation). The optimal interval for blood pressure screening has not been determined and is left to clinical discretion. Current expert opinion is that adults who are believed to be normotensive should receive blood pressure measurements at least once every 2 years if their last diastolic and systolic blood pressure readings were below 85 and 140 mm Hg, respectively, and annually if the last diastolic blood pressure was 85-89 mm Hg. ¹ Sphygmomanometry should be performed in accordance with recommended technique. ¹ Hypertension should not be diagnosed on the basis of a single measurement elevated readings should be confirmed on more than one reading at each of three separate visits. In adults, current blood pressure criteria for the diagnosis of hypertension are an average diastolic pressure of 90 mm Hg or greater and/or an average systolic pressure of 140 mm Hg or greater. ¹ Once confirmed, patients should receive appropriate counseling regarding physical activity ( Chapter 55), weight reduction and dietary sodium intake ( Chapter 56), and alcohol consumption ( Chapter 52). Evidence should also be sought for other cardiovascular risk factors, such as elevated serum cholesterol (Chapter 2) and smoking ( Chapter 54), and appropriate intervention should be offered when indicated. The decision to begin drug therapy may include consideration of the level of blood pressure elevation, age, and the presence of other cardiovascular disease risk factors (e.g., tobacco use, hypercholesterolemia), concomitant disease (e.g., diabetes, obesity, peripheral vascular disease), or target-organ damage (e.g., left ventricular hypertrophy, elevated creatinine). ^1,106,108 Antihypertensive drugs should be prescribed in accordance with recent guidelines ^1,106,108 and with attention to current techniques for improving compliance. ^53,54

Measurement of blood pressure during office visits is also recommended for children and adolescents ("B" recommendation). This recommendation is based on the proven benefits from the early detection of treatable causes of secondary hypertension there is insufficient evidence to recommend for or against routine periodic blood pressure measurement to detect essential (primary) hypertension in this age group. Sphygmomanometry should be performed in accordance with the recommended technique for children, and hypertension should only be diagnosed on the basis of readings at each of three separate visits. ¹⁸ In children, criteria defining hypertension vary with age. ¹⁸ Age-, sex-, and height-specific blood pressure nomograms for U.S. children and adolescents have been published. ²⁰

Routine counseling to promote physical activity ( Chapter 55) and a healthy diet ( Chapter 56) for the primary prevention of hypertension is recommended for all children and adults.

The draft update of this chapter was prepared for the U.S. Preventive Services Task Force by Carolyn DiGuiseppi, MD, MPH, based in part on material prepared for the Canadian Task Force on the Periodic Health Examination by Alexander G. Logan, MD, FRCPC, and Christopher Patterson, MD, FRCPC.

Cerebrovascular disease is the third leading cause of death in the U.S., accounting for over 149,000 deaths in 1993. ¹ Most stroke-related morbidity and mortality occur in older adults: 87% of all deaths and 74% of all hospitalizations occur in persons age 65 years or older. ² Strokes can result in substantial neurologic deficits as well as serious medical and psychological complications. With an estimated prevalence of 3 million stroke survivors, ³ this illness places enormous burdens on family members and caretakers, often necessitating skilled care in an institutional setting. The direct and indirect costs of stroke in the U.S. have been estimated at $30 billion annually. ⁴ The principal risk factors for ischemic stroke are increased age, hypertension, smoking, coronary artery disease, atrial fibrillation, and diabetes. ^4-7 Of these, the most important modifiable risk factors are hypertension and smoking. ⁸ Improved treatment of high blood pressure has been credited with the greater than 50% reduction in age-adjusted stroke mortality that has been observed since 1972 (see Chapter 3).

Population-based cohort studies have established that persons with carotid artery stenosis are at increased risk for subsequent stroke, myocardial infarction (MI), and death. ^9,10 The risk of stroke is greatest for persons with neurologic symptoms such as transient ischemic attacks (TIAs), but is also increased in patients with asymptomatic lesions. The prevalence of hemodynamically significant carotid stenosis varies with age and other risk factors: population-based studies estimate that 0.5% of persons in their 50s and about 10% of those over age 80 have carotid stenosis greater than 50%. ¹¹ The proportion of all strokes attributable to previously asymptomatic carotid stenosis seems to be small, however. In a study of 250 patients over age 60 with cerebral infarction, only 13% had ipsilateral carotid stenosis of 70% or greater. ¹²

Two methods are used to screen for carotid artery stenosis: clinical auscultation for carotid bruits and noninvasive studies of the carotid artery. Neck auscultation is an imperfect screening test for carotid stenosis. There is considerable interobserver variation among clinicians in the interpretation of the key auditory characteristics -- intensity, pitch, and duration -- of importance in predicting stenosis. ¹³ In addition, a cervical bruit can be heard in 4% of the population over age 40, but the finding is not specific for significant carotid artery stenosis. Between 40% and 75% of arteries with asymptomatic bruits do not have significant compromise in blood flow ¹⁴ similar sounds can also be produced by anatomic variation and tortuosity, venous hum, goiter, and transmitted cardiac murmur. ^13,15-17 Finally, hemodynamically significant stenotic lesions may exist in the absence of an audible bruit. ^13,15,18 Using 70-99% stenosis on a carotid angiogram as a reliable standard, a carotid bruit has a sensitivity of 63-76% and a specificity of 61-76% for clinically significant stenosis. ¹⁹

Persons with cervical bruits can be evaluated further with greater accuracy by noninvasive study of the carotid arteries. Older techniques (e.g., spectral analysis phonoangiography, continuous-wave or pulsed Doppler ultrasound, B-mode real-time ultrasound, oculoplethysmography, ophthalmodynamometry, periorbital directional Doppler ultrasound, and thermography) have been replaced largely by carotid duplex sonography which combines the capabilities of B-mode and Doppler ultrasound. A 1995 meta-analysis of 70 studies comparing the accuracy of noninvasive diagnostic tests to carotid angiography (the reference standard) concluded that carotid duplex, carotid Doppler, and magnetic resonance angiography (MRA) were equally effective in diagnosing carotid stenosis of 70% or greater: estimated sensitivity ranged from 83% to 86%, specificity from 89% to 94%. ²⁰ Depending on the underlying population characteristics, the positive predictive value of carotid duplex ranges from 82% to 97%. ²¹ The performance of noninvasive tests for screening asymptomatic persons, however, has not been assessed in a prospective study. Although MRA seems to be quite sensitive and spares patients the risks of conventional angiography, it is unlikely to be a useful screening test due to costs (over $400) and inconvenience. ²²

The rationale for testing for carotid artery stenosis is that persons with asymptomatic stenoses are not only at increased risk for cerebrovascular disease, ^11,12 but that early detection can reduce morbidity due to cerebrovascular disease. According to this rationale there are several benefits to early detection of asymptomatic carotid stenosis. An awareness of the diagnosis might motivate patients to modify other risk factors (e.g., high blood pressure, smoking, physical inactivity). Performing carotid endarterectomy in some individuals might prevent subsequent cerebral infarction distal to the obstruction. Finally, antiplatelet drugs (aspirin and ticlopidine) might reduce stroke risk in asymptomatic individuals with carotid artery stenosis. No study has specifically compared a strategy of screening and early intervention in asymptomatic persons to intervening only in symptomatic patients (e.g., those with TIAs). The first symptom of carotid stenosis in some patients may be an irreversible stroke, however. A number of studies have examined whether interventions in asymptomatic persons can reduce the subsequent incidence of fatal and nonfatal stroke.

A bruit over the carotid artery is a fair indicator of vascular disease but a poor predictor that ischemic stroke will occur in its arterial distribution. The proportion of persons with asymptomatic bruits who will experience stroke is small: the annual incidence of stroke ipsilateral to a bruit and unheralded by TIAs is only 1-3%. ^{9,10,16,23-25} Higher grades of stenosis (assessed by sonography) are associated with increasing risk of neurologic events, rising to 5-7% per year with high-grade stenosis or total occlusion. ^26,27 However, in those persons who will suffer a stroke, the degree of carotid stenosis does not always predict the risk of cerebral infarction, ^16,23,28 or its location. ^11,12 Carotid artery lesions may be less a predictor of atherothrombotic strokes than of generalized atherosclerotic disease persons with carotid artery disease are considerably more likely to die from ischemic heart disease than from a cerebrovascular event. ^9,10

One of the major justifications for screening is the belief that carotid endarterectomy for high-grade, asymptomatic lesions detected through screening can prevent stroke. Three studies published before 1987 reported improved outcomes after endarterectomy. These studies provide poor quality evidence because they included previously symptomatic patients, were convenience samples derived from surgeons' practices, had inconsistent measurement criteria, or did not randomly assign patients. ^17,29,30 Four more recent randomized trials have compared aspirin with endarterectomy in patients with asymptomatic carotid artery stenosis. The first study comparing aspirin alone with endarterectomy alone ³¹ enrolled only 71 patients before it was terminated due to excess MI in the surgical group no conclusions could be drawn regarding the effectiveness of endarterectomy for preventing stroke. ³² The second study, the 1991 European CASANOVA trial, randomized 410 patients with moderately severe stenosis (> 50% but < 90%) to treatment with aspirin/dipyridamole or aspirin/dipyridamole plus surgery. ³³ The protocol was complex: some patients in both groups had contralateral symptoms, patients with stenosis greater than 90% were excluded, and 72 patients received therapy appropriate for the other group (more in the group randomized to surgery). There were no differences in the numbers of neurologic events and deaths between the two groups. The power of the study, however, was insufficient to exclude a clinically important benefit in the surgical group. ³³ A third study, published in 1993, randomized 444 older veterans (mean age 64) with 50% or greater carotid stenosis to aspirin plus carotid endarterectomy or aspirin therapy alone. Patients who underwent carotid endarterectomy had lower rates of ipsilateral neurologic events, the primary endpoint: the combined incidence of TIAs, transient monocular blindness, and stroke was 8% in the surgery group versus 21% with aspirin only (p < 0.001), during an average follow-up of 48 months. The two groups had similar outcomes, however, using a combined endpoint of stroke or death from any cause. The power of the study was insufficient to exclude up to a 20% reduction in stroke in the surgically treated group. ³⁴ The generalizability of this study was limited by the lack of female subjects and by the excessive morbidity and mortality in both groups (over 40% incidence of stroke or death in both groups over the 4-year follow-up).

The Asymptomatic Carotid Artery Study (ACAS), ³⁵ funded by the National Institutes of Health, recently reported final results that provide stronger evidence of the benefit of endarterectomy for asymptomatic stenoses. ³⁶ This multicenter study randomized 1662 patients with asymptomatic stenoses greater than 60% (mean stenosis 73%) to endarterectomy plus aspirin or to aspirin alone. Most patients (87%) were over age 60, and more than two thirds had coronary heart disease. The trial was stopped after a median follow-up of 2.7 years. The estimated 5-year risk for ipsilateral stroke or perioperative stroke or death was 5.1% for surgical patients and 11% for medically treated patients, a reduction in cumulative risk of 53% (95% confidence interval, 22 to 72). The absolute reduction in the combined incidence of major ipsilateral stroke, major perioperative stroke, or perioperative death, however, was considerably smaller (estimated 5-year risk of 3.4% in the surgery group vs. 6% in the medical group), not statistically significant (p = 0.13), and evident only in the fifth year of follow-up. Subgroup analyses suggest that endarterectomy may be less effective in women than in men (17% vs. 66% reduction in 5-year event rate), possibly due to higher perioperative complication rates (3.6% in women vs. 1.7% in men) neither of these differences between genders was statistically significant, however. The medical centers participating in this trial had been rigorously evaluated for the quality of patient management, and only surgeons with a perioperative complication rate of less than 3% among asymptomatic patients were allowed to participate. ³⁷ Published studies have reported a perioperative mortality ranging from 1% to 3%, ^33,34,38-40 and a perioperative stroke rate ranging between 2% and 10%, depending on patient characteristics and surgical expertise. ^{13,33,34,39-44} In six prospective trials of endarterectomy published after 1990, perioperative complication rates (stroke and death combined) range from 3% to 8%. ³⁸ Complication rates seem to be lower in asymptomatic patients than in symptomatic patients, however. ^38,40 A fifth trial of surgery versus medical management for asymptomatic carotid artery stenosis is still in progress. ¹¹

Antiplatelet therapy with aspirin or ticlopidine offers a second possible intervention to reduce the risk of stroke in patients with asymptomatic carotid artery stenosis. Clinical trials have demonstrated a benefit of aspirin in reducing stroke among symptomatic patients (i.e., in persons with TIAs or stroke), ^45-48 but observed no benefit on stroke in a large trial in asymptomatic physicians (prevalence of carotid disease unknown). ⁴⁹ Among patients with asymptomatic carotid disease, who have a lower risk of ischemic events than do symptomatic patients, chronic aspirin therapy may not provide sufficient benefits to justify the documented risks of hemorrhagic complications (see Chapter 69). A multicenter prospective study comparing aspirin to placebo in asymptomatic patients with >50% carotid stenosis found no difference in stroke rates. ⁵⁰ Ticlopidine is an alternative to aspirin in patients with risk factors for gastrointestinal hemorrhage, aspirin intolerance, and in patients who continue to have vascular events despite aspirin therapy, but its use is limited by high cost and small risk of neutropenia (approximately 1%). ^51,52 The efficacy of ticlopidine in patients with asymptomatic carotid artery stenosis is not known.

Reducing serum lipids may slow the progression of carotid atherosclerosis and reduce clinical events. In a randomized trial enrolling patients with moderately elevated levels of LDL cholesterol (130-190 mg/dL) and early carotid atherosclerosis diagnosed by B-mode ultrasound, lovastatin induced regression of atherosclerosis and reduced total cardiovascular events compared to placebo. ^52a Lipid-lowering drug therapy has not been examined specifically for treatment of advanced carotid stenosis, but is generally recommended for patients with high cholesterol and symptomatic vascular disease, based on its ability to reduce coronary heart disease mortality (see Chapter 2). No controlled studies have examined changes in the behavior of patients (e.g., smoking cessation or dietary modification) on learning the results of carotid artery examinations.

Although auscultation of the carotid arteries is widely considered a routine component of the physical examination, the Canadian Task Force on the Periodic Health Examination ⁵³ recommended against screening for bruits in asymptomatic persons, based on the poor sensitivity and specificity of cervical bruits as an indicator of significant carotid stenosis. The American Academy of Family Physicians recommends auscultation for carotid bruits in people age 40 and older with risk factors for cerebrovascular or cardiovascular disease, those with neurologic symptoms (e.g., TIA) or those with a history of cardiovascular disease ⁵⁴ this policy is currently under review. The 1988 guidelines of the American College of Physicians recommend that patients with asymptomatic bruits should not have further diagnostic testing but should be educated about potential symptoms of a TIA in the carotid circulation. ⁵⁵ In 1988, an ad hoc multidisciplinary consensus panel involved in designing the ACAS study recommended a baseline noninvasive study of the carotid arteries in persons considered at high risk for extracranial carotid arterial disease. ⁵⁶ In 1992, the Ad Hoc Committee of the Joint Council of the Society for Vascular Surgery and the North American Chapter of the International Society for Vascular Surgery recommended that patients with asymptomatic carotid artery stenosis greater than 75% who are otherwise healthy and have a projected life expectancy more than 5 years should be considered for surgery if the operative morbidity and mortality rates are less than 3%. ⁵⁷

The effectiveness of routine screening and intervention to reduce morbidity from asymptomatic carotid artery disease remains uncertain. The most effective interventions to prevent stroke are smoking cessation and the identification and treatment of hypertension. Although screening will detect some patients with asymptomatic high-grade carotid lesions who may benefit from endarterectomy, such patients account for only a small proportion of all strokes. In addition, there are several reasons to be cautious about undertaking widespread screening in asymptomatic persons on the basis of the current evidence: ^11,38,58 the risk of major stroke ipsilateral to stenotic lesions is relatively low without surgery (approximately 1% per year) the absolute reduction in major stroke and death due to surgery over 5 years in ACAS was small and not conclusive surgery may result in other nonfatal complications (cranial nerve injury, MI, etc.) and the low complication rate of the ACAS-selected surgeons is not likely to reflect the typical risk of endarterectomy in the community. If complication rates of surgery are higher or underlying risk of stroke lower than reported for the ACAS study, the risks of surgery for asymptomatic carotid artery disease may outweigh the benefits. Routine screening will also subject some patients without significant carotid disease to the risks of angiography (1% risk of stroke), due to occasional false-positive results of carotid ultrasound.

As a result, it is not yet clear whether widespread screening in the primary care setting will be an effective way to reduce morbidity and mortality from stroke. Noninvasive testing for carotid artery stenosis is expensive (over $150 for carotid duplex or Doppler ultrasound) ²⁰ the cost of screening 50% of the population over age 60 in the U.S. has been estimated at over $7 billion. ⁵⁸ Auscultation for bruits involves little direct expense and may detect a majority of patients with severe stenosis, but the costs of follow-up testing of all patients with asymptomatic bruits could be substantial. Revised cost-effectiveness analyses of various screening and treatment strategies for asymptomatic carotid disease are under way. Patients most likely to benefit from screening are older men (over age 60) who have other risk factors for stroke, no contraindications to major surgery, and access to high-quality vascular surgery centers. Evidence regarding the effectiveness of antiplatelet drugs for asymptomatic persons is not yet sufficient to make a recommendation.

CLINICAL INTERVENTION

There is insufficient evidence to recommend for or against screening asymptomatic persons for carotid artery stenosis, using physical examination or carotid ultrasound ("C" recommendation). A recommendation may be made on other grounds to discuss the potential benefits of screening with high-risk patients (e.g., persons over age 60 at high risk for vascular disease), provided that high-quality vascular surgical care is available (surgical morbidity and mortality less than 3%). These other grounds include the increased prevalence of significant carotid disease, and the possible long-term benefit of endarterectomy in patients with asymptomatic stenosis greater than 60% when performed by qualified surgeons. Patients should be screened and counseled about other risk factors for cerebrovascular disease as discussed in other chapters (see Chapters 3 and 54).

The draft update of this chapter was prepared for the U.S. Preventive Services Task Force by Stephen Tabet, MD, MPH, Alfred O. Berg, MD, MPH, and David Atkins, MD, MPH.

Peripheral arterial disease (PAD) becomes increasingly common with age. An estimated 12-17% of the population over age 50 have PAD. ^1-4 Increased mortality has been well documented in patients with PAD, a disease that is strongly associated with coronary artery disease and that shares many of the same risk factors. ^1,2,5-9 Although only a small proportion of individuals with PAD and intermittent claudication develop skin breakdown or limb loss, pain and associated disability often restrict ambulation and the overall quality of life. ^1,5 Persons at increased risk for PAD include cigarette smokers and persons with diabetes mellitus or hypertension. ^1,5,9,10 Diabetic PAD is responsible for about 50% of all amputations. ¹

There is evidence that a history of intermittent claudication and the palpation of peripheral pulses are unreliable techniques for the detection of PAD. ^1,3,8,11 In one study, a battery of noninvasive tests for PAD was administered to 624 hyperlipidemic subjects aged 38-82. ⁷ In this population, the sensitivity and positive predictive value of a classic history of claudication were only 54% and 9%, respectively, when compared with the results of formal noninvasive testing. The sensitivity of an abnormal posterior tibial pulse was 71%, the positive predictive value was 48%, and the specificity was 91%. An abnormal dorsalis pedis pulse had a sensitivity of only 50% this artery is congenitally absent in 10-15% of the population. ¹¹ The authors concluded that symptoms and abnormal pulses are not pathognomonic for PAD. ⁷ Greater accuracy has been achieved with noninvasive testing using Doppler ankle-arm pressure ratios, measurement of reactive hyperemia after exercise, pulse reappearance time, ultrasound duplex scanning, and plethysmography. ^1,5,12,13 At present, however, additional data on sensitivity, specificity, and positive predictive value of these tests in asymptomatic populations are needed before noninvasive testing can be considered for routine screening.

Because surgery for PAD is offered only to patients with symptomatic disease, the rationale for the early detection of asymptomatic PAD is that risk factor modification following detection might lower subsequent morbidity and mortality from PAD and systemic atherosclerotic disease. By virtue of its strong association with coronary atherosclerosis and coronary events, ⁵ the early diagnosis of PAD might also lead to the detection of asymptomatic coronary heart disease. Evidence of these benefits is lacking, however. There has been no research to examine whether the detection and treatment of asymptomatic persons with PAD reduces the morbidity or mortality observed in symptomatic patients. It is clear that certain interventions are beneficial in symptomatic persons. There is evidence, for example, that patients who stop smoking have marked improvement in PAD symptoms and reduced overall cardiovascular mortality. ^1,14 Certain antithrombotic drugs may also be of benefit. ¹⁵ It is unknown whether treatment measures used in symptomatic patients are beneficial in asymptomatic patients. ^1,6 Examples include walking programs, control of weight and blood pressure, correction of elevated serum lipids and glucose, proper foot care, and certain drugs.

There are no official recommendations for physicians to screen asymptomatic persons for PAD, although inspection of the skin and palpation of peripheral pulses are often included in the physical examination of the extremities. A recent international workshop sponsored by the American Diabetes Association and American Heart Association recommends annual screening for PAD in patients with diabetes. ¹⁶

Evidence is lacking that routine screening for PAD in asymptomatic persons is effective in reducing morbidity or mortality from this disease. Many of the behavioral interventions that might be prescribed after detecting PAD -- smoking cessation (Chapter 54), blood pressure control (Chapter 3), and exercise (Chapter 55) -- can be recommended without screening and are of proven value in the prevention of other atherosclerotic conditions, such as coronary heart and cerebrovascular disease. Screening by physical examination in the general population of asymptomatic adults, where the prevalence of PAD is low, is likely to produce a substantial number of false-positive results. Positive screening results will necessitate expensive noninvasive tests and may lead to potentially hazardous invasive tests such as arteriography. At the same time, it is not known whether the early detection of PAD in asymptomatic patients will result in more effective treatment of risk factors or better outcomes.

CLINICAL INTERVENTION

Routine screening for peripheral arterial disease in asymptomatic persons is not recommended ("D" recommendation). Clinicians should screen for hypertension (see Chapter 3) and hypercholesterolemia (Chapter 2), and they should provide appropriate counseling regarding the use of tobacco products (Chapter 54), physical activity (Chapter 55), and nutritional risk factors for atherosclerotic disease (Chapter 56). Clinicians should be alert to symptoms of PAD in persons at increased risk (persons over age 50, smokers, diabetics) and evaluate patients who have clinical evidence of vascular disease.

The draft update of this chapter was prepared for the U.S. Preventive Services Task Force by Stephen Tabet, MD, MPH, and Alfred O. Berg, MD, MPH.

Approximately 8,700 deaths from abdominal aortic aneurysm (AAA) were reported in the U.S. in 1990, ¹ but undiagnosed ruptured aneurysms are probably responsible for many additional cases of sudden death in older persons. Once rupture occurs, massive intraabdominal bleeding is usually fatal unless prompt surgery can be performed. A review of six case-series including 703 cases of ruptured aneurysm estimated that only 18% of all patients with ruptured AAA reached a hospital and survived surgery. ² The large majority of deaths from AAA occur in older men and women men over 60 and women over 70 accounted for 95% of all deaths from AAA in a recent report. ² Approximately 0.8% of male deaths and 0.3% of female deaths among persons over 65 years of age in the U.S. were attributed to AAA in 1990. ¹

An aneurysm is usually defined as a focal dilation of the aorta at least 150% of the normal aortic diameter. ³ Given a normal aortic diameter in older men of 2 cm (range 1.4-3.0 cm), ⁴ an aortic diameter above 3 cm usually indicates an aneurysm. The pathogenesis of aneurysms is not completely understood, but well-established risk factors for AAA include increasing age, male gender, and family history of aneurysms. ³ The male to female ratio for death from AAA is 11:1 between ages 60 and 64 and narrows to 3:1 between ages 85 and 90. ⁵ Other possible risk factors include tobacco use, hypertension, peripheral vascular disease, and presence of peripheral arterial aneurysms. ^3,6-8 In populations over age 60, estimates of prevalence range from 2% to 8% and increase with age. ^8-10 A recent community study in England screened nearly 9,000 men and women aged 65-80 with ultrasound: 7% of men and 1% of women had an aneurysm at least 3 cm in diameter. ¹¹ Among all patients, only 0.6% had aneurysms 5 cm or larger, and only 0.3% had aneurysms of 6 cm or more. ¹¹ There are only limited data on the incidence of new aneurysms in a previously screened population. In one study, 189 men who had a normal ultrasound at age 65-66 years were rescreened 5 years later only 2 (1%) had an aortic diameter greater than 3 cm. ¹²

Few aneurysms less than 4 cm in diameter will rupture. ^2,13,14 Overall, 3-6% of aneurysms greater than 4 cm in diameter will rupture annually, ^14,15 but the rate of rupture is directly related to the size of the aneurysm. The natural history of most aneurysms is one of gradual enlargement growth rates have been estimated to average 0.2 cm/year for aneurysms under 4 cm, and 0.5 cm/year for those over 6 cm. ⁸

Two tests, palpation of the abdomen during physical examination and abdominal ultrasound, have been seriously advocated as screening tests for AAA. Other tests that can detect aneurysms -- plain radiographs of the abdomen, computed tomography (CT), and magnetic resonance imaging (MRI) -- are either not sensitive enough or are too expensive to be practical for screening in asymptomatic populations.

The accuracy of physical examination in detecting AAA is not completely known. Large aneurysms are easier to detect than small ones, and it is easier to detect aneurysms in thin people. Estimates of the sensitivity of physical examination in detecting AAA range from 22% to 96%. ^17,18 The high sensitivity obtained in series of preoperative cases probably represents the preponderance of large aneurysms in this population. Lederle reported a sensitivity of 50% and a positive predictive value of 35% in a high-risk population screened in an internal medicine clinic (9% prevalence of AAA). ¹⁹ Four of five aneurysms greater than 5 cm diameter in this series were detected by palpation. In contrast, Allen reported a 22% sensitivity, 94% specificity, and positive predictive value of 17% in a population with a 5% prevalence of aneurysms. ¹⁷ No large-scale community-based studies of screening for AAA by physical examination have been reported.

Ultrasound is an extremely sensitive and specific test for AAA of all sizes, at least in cases where the diagnosis and size of the aneurysm can be confirmed at surgery. Reported sensitivities range from 82% to 99%, with sensitivity approaching 100% in some series of patients with a pulsatile mass. ¹⁶ In a small proportion of patients, visualization of the aorta will be inadequate due to obesity, bowel gas, or periaortic disease. Although ultrasound screening is noninvasive and relatively simple, compliance with invitations to be screened has been variable (50-64% attendance) in community screening trials. ^7,11 Diagnostic abdominal ultrasound is currently expensive in the U.S. ($100-$175 per examination), but screening for AAA alone could probably be performed much more quickly and cheaply. ²

No prospective or retrospective controlled trials of screening for AAA that include outcome data have yet been reported. A pilot trial in England that offered screening at random to older subjects has enrolled 15,000 men and women, but it may not have sufficient power to prove a benefit in mortality. ⁸ The difficulty of identifying all deaths caused by AAA, combined with varying compliance with screening, may make it difficult to conduct definitive controlled trials of AAA screening. ^8,20

Surgical resection and repair with an artificial graft is a very effective treatment for AAA. Among 13 large case-series of surgery for nonruptured aneurysms published since 1980, overall surgical mortality was 4% (range 1.4-6.5%) mortality during emergency surgery for rupture is much higher, averaging 49% (range 23-69%). ³ Mortality after elective surgery is often due to underlying cardiovascular disease in patients with AAA. If the patient survives the immediate postoperative period, long-term survival is comparable to similar persons without aneurysms, but late postoperative complications (graft infection, graft occlusion, and aortoenteric fistula) may result in additional deaths and morbidity. ³ The high prevalence of cardiovascular disease in patients with AAA and competing causes of morbidity and mortality in older patients may diminish the benefit of detecting asymptomatic aneurysms in older populations. Of 124 patients aged 65-80 who had large aneurysms detected in a community screening program, 27% were deemed unfit for surgery or died of other causes before surgery. ¹¹ In recent series, up to 40% of patients undergoing surgery for nonruptured aneurysms had died within 6 years after surgery, primarily due to coronary heart disease or stroke. ^3,21

Risk of elective surgery must be balanced against the risk of rupture of an untreated aneurysm, which is directly related to aneurysm size. Most vascular surgeons currently recommend surgery for asymptomatic aneurysms 5 cm or larger, since the risk of rupture (25-41% over 5 years) is substantially higher than risks from surgery. ³ While more aggressive management of smaller aneurysms (4-5 cm) has been recommended by some, ²² others have suggested that asymptomatic, slow-growing aneurysms under 6 cm can be successfully followed by serial ultrasound. ^2,11 A large community-based screening program, which employed this conservative strategy over 8 years, observed two cases of rupture among 29 subjects with aneurysms 5-5.9 cm, for a rate of 1.5%/year. ^11,23 A model fitted to data from 13 studies of untreated aneurysms supports a relatively low risk of rupture in aneurysms less than 6 cm estimated annual rates of rupture for aneurysms 4-4.9, 5-5.9, 6-6.9, and over 7 cm were 1%, 3%, 9%, and 25%, respectively. ² These data, which are based largely on incidentally detected cases, may not reflect accurately the prognosis of asymptomatic aneurysms discovered by routine ultrasound screening. Furthermore, decisions to forgo surgery in patients with larger aneurysms were likely to have been influenced by factors (e.g., age, comorbidity, lack of symptoms) that may have independently influenced the risk of rupture. Trials are currently ongoing to determine the optimal management of patients with AAA that are 4-5.4 cm in size. ²⁴

The Canadian Task Force on the Periodic Health Examination ⁷ concluded that there was poor evidence to include or exclude screening for AAA in the periodic health examination of asymptomatic individuals. They noted that targeted physical examination may be considered prudent for men over 60, however, and that ultrasound screening could be considered in selected high-risk men over 60: smokers with other risk factors for AAA (hypertension, claudication, family history, or other vascular disease).

No prospective or retrospective controlled trials of screening for AAA have yet been reported that include data on mortality or other clinical outcomes. At present, the only effective intervention available for patients with aneurysms is major abdominal surgery. Until further data are available from population-based screening trials, it is uncertain whether the projected benefit from preventing ruptured aneurysms is sufficient to justify the costs of widespread screening and the potential risks from increased surgery. While there is general consensus that resection is indicated for incidentally discovered, large aneurysms (6 cm or larger), these are relatively uncommon in the general population the appropriate management of smaller (4-5 cm) aneurysms remains controversial. Data from older case series may not be a reliable guide to the natural history of asymptomatic aneurysms discovered by ultrasound. For many older patients with small aneurysms, the risk of dying from coronary heart disease or stroke is much higher than the risk from ruptured AAA. ²¹

The benefits of routine screening will depend on other parameters that merit further research: the proportion of clinically important aneurysms that are detected without screening the sensitivity and specificity of abdominal palpation for detecting AAA in the primary care setting risk factors for rapid growth or rupture of AAA and long-term morbidity of patients undergoing elective surgery. Patient compliance with recommendations for follow-up or surgery will also directly influence the ability of screening to prevent ruptured aneurysms.

A recent cost-effectiveness analysis compared different screening protocols in a high-risk population of men between 60 and 80 years of age. ²⁵ The authors concluded that a single screen for AAA by abdominal palpation might be considered cost-effective, but it would be of small clinical benefit (average increase in life expectancy of 0.002 year). A single screen with ultrasound was at the high end of the cost range that might be considered cost-effective ($41,550/year of life gained), and repeat screening was not cost-effective. They noted that, due to the variable quality of the available data, screening for AAA could prove to be very cost-effective or could actually cause a net harm. If low-cost screening ultrasound were available (vs. $150 average charge for diagnostic ultrasound in the U.S.), ultrasound screening would be much more cost-effective, and preferable to physical examination. ²⁵

CLINICAL INTERVENTION

There is insufficient evidence to recommend for or against routine screening for abdominal aortic aneurysms with abdominal palpation or ultrasound ("C" recommendation). Recommendations against routine ultrasound screening in the general population may be made on other grounds, such as the low prevalence of clinically significant AAA and the high cost of screening. Although direct evidence that screening for AAA reduces mortality or morbidity is not available in any population, clinicians may decide to screen selected high-risk patients, due to the significant burden of disease and the availability of effective surgical treatment for large aneurysms. Men over age 60 who have other risk factors (e.g., vascular disease, family history of AAA, hypertension, or smoking) are at highest risk for AAA and death due to ruptured aneurysms. Screening is not indicated for patients who are not appropriate candidates for major abdominal surgery (e.g., those with severe cardiac or pulmonary disease). If screening is performed, it is not certain whether ultrasound or abdominal palpation is the preferred test. Abdominal palpation is less expensive but also less sensitive than ultrasound. Cost-effectiveness analysis suggests that repeat examination of individuals with a previous normal ultrasound is not indicated. ²⁴

The draft of this chapter was prepared for the U.S. Preventive Services Task Force by Paul S. Frame, MD, and David Atkins, MD, MPH.

In the U.S. in 1995, there were an estimated 182,000 new cases of breast cancer diagnosed and 46,000 deaths from this disease in women. ¹ Approximately 32% of all newly diagnosed cancers in women are cancers of the breast, the most common cancer diagnosed in women. ¹ The annual incidence of breast cancer increased 55% between 1950 and 1991. ² The incidence in women during the period 1987-1991 was 110/100,000. ² In 1992, the annual age-adjusted mortality from breast cancer was 22/100,000 women. ³ The age-adjusted mortality rate from breast cancer has been relatively stable over the period from 1930 to the present. ^1,2 For women, the estimated lifetime risk of dying from breast cancer is 3.6%. ² Breast cancer resulted in 2.2 years of potential life lost before age 65 per 1,000 women under age 65 in the U.S. during 1986-1988. ⁴ This rate was surpassed only by deaths resulting from motor vehicle injury and infections. Breast cancer is the leading contributor to cancer mortality in women aged 15-54, ¹ although 48% of new breast cancer cases and 56% of breast cancer deaths occur in women age 65 and over. ² As the large number of women in the "baby boom" generation age, the number of breast cancer cases and deaths will increase substantially unless age-specific incidence and mortality rates decline.

Important risk factors for breast cancer include female gender, residence in North America or northern Europe, and older age. ⁵ In American women, the annual incidence of breast cancer increases with age: 127 cases/100,000 for women aged 40-44 229/100,000 for women aged 50-54 348/100,000 for women aged 60-64 and 450/100,000 for women aged 70-74. ² The risk for a woman with a family history of breast cancer in a first-degree relative is increased about 2-3-fold, and for women under 50 it is highest when the relative had premenopausally diagnosed breast cancer. ^6-9 Women with previous breast cancer or carcinoma in situ and women with atypical hyperplasia on breast biopsy are also at significantly increased risk. ^6,7,10-12 Other factors associated with increased breast cancer risk include a history of proliferative breast lesions without atypia on breast biopsy, late age at first pregnancy, nulliparity, high socioeconomic status, and a history of exposure to high-dose radiation. ^6,7,10-12 Associations between breast cancer and oral contraceptives, long-term estrogen replacement therapy, obesity, and a diet high in fat have been suggested, but causal relationships have not been established. ^6,7,13,14

The three screening tests usually considered for early detection of breast cancer are clinical breast examination (CBE), x-ray mammography, and breast self-examination (BSE). Estimates of the sensitivity and specificity of these maneuvers depend on a number of factors, including the size of the lesion, the characteristics of the breast being examined, the age of the patient, the extent of follow-up to identify false negatives, the skill and experience of the examiner or radiographic interpreter, and (in the case of mammography) the quality of the mammogram. Because multiple clinical trials have demonstrated the effectiveness of screening, measures of screening test performance (such as sensitivity and specificity) are primarily helpful in comparing trials, screening programs, and community practice. Uniform definitions, however, are necessary for such comparisons. For example, different studies may use similar definitions of sensitivity, such as the number of screen-detected cancers compared to the total of screen-detected cancers plus interval cancers, but one may use a fixed interval (e.g., 12 months) ¹⁵ and another a variable interval (e.g., time to next screen), ¹⁶ making direct comparisons difficult. The ability to detect interval cancers may also vary and will affect such estimates.

A review ¹⁷ of the current clinical trial data, published and unpublished, summarized screening test performance for mammography using uniform definitions. Sensitivity of mammography did not dramatically differ across the trials. Estimates from three Swedish trials using mammography alone averaged about 75%, while estimates for mammography combined with CBE ranged from 75% in the Health Insurance Plan of Greater New York (HIP) to 88% in the Edinburgh trial and the Canadian National Breast Cancer Screening Study in women aged 50-59 (NBSS 2). Specificity estimates ranged from 98.5% in the HIP trial to 83% in the Canadian NBSS 2. Sensitivity estimates for mammography alone and for combined screening with CBE have generally been 10-15% lower for women aged 40-49 compared with women greater than age 50. ^15,17-19 Preliminary results from two North American demonstration projects suggest improved sensitivity of mammography, especially for women in their forties, with current mammographic techniques. ²⁰ Significant variations in interpreter performance have also been observed. ^21-23 In the Canadian trials, agreement was about 50% beyond that attributable to chance between radiologists at five screening centers and a single reference radiologist. ²¹

The effectiveness of CBE alone has not been evaluated directly, but comparisons of the sensitivity and specificity of this maneuver to that of mammography can be considered. The Canadian NBSS 2 was designed to assess the incremental value of mammography above a careful, thorough (5-10 minutes) CBE. ^24,25 Preliminary results showing no incremental benefit highlighted the fact that higher sensitivity (88% for mammography plus CBE vs. 63% for CBE alone) ¹⁷ may not guarantee improved effectiveness. Specificity was comparable or slightly better for CBE alone. Sensitivity of CBE for women aged 40-49 (Canadian NBSS 1) was about 10% lower at initial screen compared to the estimate for women aged 50-59 (Canadian NBSS 2). ²⁶ Specificity estimates were similarly lower for younger women.

Data regarding the accuracy of BSE are extremely limited. One report calculated an upper limit of sensitivity ranging from 12 to 25% by assuming all interval cases in the clinical trials were detected by BSE. ¹⁷ Using a similar approach, the overall sensitivity of BSE alone was estimated to be 26% in women also screened by mammography and CBE in the Breast Cancer Detection Demonstration Project (BCDDP). ²⁷ Estimated BSE sensitivity decreased with age, from 41% for women aged 35-39 to 21% for women aged 60-74. ²⁷ Thus, as currently practiced, BSE appears to be a less sensitive form of screening than is CBE or mammography, and its specificity remains uncertain. The sensitivity of BSE can be improved by training, as measured by the proportion of benign lumps ²⁸ detected on human models and artificial lumps ²⁹ on silicone breast models, although whether this improved detection on models translates into improved personal BSE performance is unknown.

Adverse effects of screening tests are an important consideration. False-positive tests, resulting from the effort to maximize disease detection, may have negative consequences including unnecessary diagnostic tests. In the Canadian trials there were 7-10% false positives from combined screening with mammography and CBE among women aged 40-49 and 4.5-8% among those aged 50-59. ^24,30 In a study of the yield of a first mammographic screening among women, half as many cancers per 1,000 first screening mammograms were diagnosed in women aged 40-49 (3/1,000) compared to women aged 50-59 (6/1,000). ³¹ Yet, women aged 40-49 underwent twice as many diagnostic tests per cancer detected compared to women aged 50-59 (43.9 vs. 21.9). Women aged 60-69 had a higher yield from screening, with 13 breast cancers diagnosed per 1,000 first screening mammograms and 10.2 diagnostic tests performed per cancer detected.

Mammographic screening may also adversely affect psychological well-being. Increased anxiety about breast cancer after a false-positive mammogram has been reported both at short- and long-term follow-up in studies surveying groups of screened women. ^32,33 No impact on compliance in obtaining future screening examinations was observed, however. Women who underwent a surgical biopsy as a result of a false-positive screening mammogram were more likely to report their workup as a stressful experience than were those who did not have a biopsy. ³²

Excess breast cancers in populations that received doses of ionizing radiation significantly greater than currently delivered by mammography, such as survivors from atomic bombing in Japan ³⁴ and patients with benign breast disease, ³⁵ have raised concerns about the potential radiation risk from screening mammograms. There is no direct evidence of an increased risk of breast cancer from mammographic screening, however. Assuming a mean breast dose of 0.1 rad from a mammogram and extrapolating from higher doses of radiation, modeling suggests that in a group of 100,000 women receiving annual screening from ages 50 to 75, 12.9 years would be lost due to radiogenic cancers but 12,623 years would be gained through a 20% reduction in breast cancer mortality as a result of that screening. ³⁴

Fewer data are available regarding adverse effects associated with CBE and BSE. A dramatic increase in false-positives was observed after instruction in BSE in a nonrandomized controlled trial evaluating performance on human models, ²⁸ although no increase was found in a randomized controlled trial evaluating performance on silicone breast models. ²⁹ The latter study also assessed the impact of training on variables other than detection performance on models. Adverse effects, such as unnecessary physician visits, heightened anxiety levels, or increased radiographic and surgical procedures, were not observed. ²⁹

Seven randomized controlled trials ^16,30,36-40 have evaluated the effectiveness of screening for breast cancer in women by either mammography alone or combined with CBE compared to no periodic screening. The age of participants at date of first invitation ranged from 40 to 74. The six trials ^16,36-40 that included women aged >=50 showed a reduction in breast cancer mortality of 20-30% in the intervention group. The reduction was statistically significant in the Health Insurance Plan of Greater New York (HIP), ³⁷ the Swedish two-county trials, ¹⁶ an overview of the Swedish trials, ⁴⁰ and two meta-analyses of the trials. ^41,42

The results of these six trials including women aged >=50 have convincingly demonstrated the effectiveness of mammographic screening (with or without CBE) for breast cancer in women aged 50-69. The HIP trial screened women aged 40-64 with annual CBE and two-view mammography. ³⁷ For women who were over age 50 at the time of entry into the study, mortality from breast cancer in the intervention group was more than 50% lower than in the control group at 5 years, decreasing to a 21% difference after 18 years of follow-up. The Edinburgh trial ³⁶ screened women aged 45-64 from 84 general medicine practices with two-view mammography and CBE on the initial screen followed by annual CBE and biennial single-view mammography. Preliminary results at seven years found a relative risk of 0.80 (95% confidence interval [CI], 0.54 to 1.17) for women aged 50 and older at entry. The results from 10-year follow-up showed little change. ¹⁷ An overview pooled the data through 1989 from the four Swedish randomized controlled trials of breast cancer screening with mammography alone. ⁴⁰ All women diagnosed with breast cancer before randomization were excluded and endpoints were independently reviewed. Breast cancer mortality was reduced by about 30% for women aged 50-69 at entry using an endpoint of breast cancer as the underlying cause of death. A meta-analysis that included the most recently published results of these trials reported a 23% reduction in breast cancer mortality for women aged 50 and older. ⁴² A meta-analysis of European case-control studies done within screening mammography programs also reported significantly reduced breast cancer mortality among women aged 50 and older. ⁴²

There are few data regarding the optimal periodicity of screening in this age group. Although an annual interval has been recommended by many groups, an analysis of data from the Swedish two-county study found little evidence that an annual interval would confer greater benefit than screening every 2 years for women over the age of 50. ¹⁹ This trial used mammography alone, but the reduction in breast cancer mortality was similar to that seen in the trials combining CBE with mammography. ^36,37 The similar mortality reductions found in screening trials using periodicities ranging from 12 to 33 months in women aged >=50 suggests that biennial screening intervals are as effective as annual intervals. In a meta-analysis of the trials evaluating screening mammography, ⁴² the estimated reduction in breast cancer mortality was the same (23%) for screening intervals of 12 months and 18-33 months in women aged 50-74.

There is limited and conflicting evidence regarding the benefit of screening women aged 70-74. The Swedish two-county trial and BCDDP time series included women up to age 74 at entry, and each found a reduction of breast cancer mortality for the intervention group as a whole. ^16,44 The Swedish overview, however, reported a relative risk of 0.98 (95% CI, 0.63 to 1.53) at 12-year follow-up for the age subgroup 70-74. ⁴⁰ The wide confidence interval, due to small numbers in this subgroup analysis, does not preclude the possibility of a substantial benefit from screening in this age group. No clinical trials have evaluated screening in women over 74 years of age at enrollment.

Although all six trials found a benefit of screening among the total group of enrolled women who were 40-74 years at entry, ^16,36-40 there is uncertainty about the effectiveness of screening women between the ages of 40 and 49. The Canadian NBSS 1 was specifically designed to address this uncertainty. ³⁰ This trial compared combined annual mammography and CBE to an initial CBE among women aged 40-49 at entry. At 7-year follow-up, no benefit of annual screening was observed (RR = 1.36 95% CI, 0.84 to 2.21). This Canadian trial has been the subject of much criticism. ^45-47 Possible irregularities with randomization have been refuted by its investigators. ⁴⁸ An independent review is planned by the National Cancer Institute of Canada to determine whether the randomization was compromised. Although mammography quality issues have also been a concern, there is little evidence to suggest that the practices were inconsistent with the standards of the other clinical trials or community practice at the time of the study. ⁴⁸ In addition, improvement in mammographic quality over the course of the study period was noted by both inside and outside observers. ⁴⁸ The proportion of controls receiving mammography, 26%, can be compared to available estimates of 13% in the two-county trial, 24% in the Malmo trial (35% for women 45-49), and 24% in the Stockholm trial. ^38,39,49 This contamination may nevertheless have reduced the trial's ability to detect a benefit from the screening intervention. An excess of node-positive cancers detected in the intervention group raised concerns about subject randomization. ³⁰ While this may have been the result of chance, other contributing factors suggested by the investigators include under-ascertainment secondary to lower surgical dissection rates in the control group and incomplete breast cancer ascertainment at preliminary follow-up (although these possibilities are unlikely to account for all of the observed excess). ⁴⁸ Although the effect of these factors should diminish with long-term follow-up, the results are unlikely to achieve statistical significance because sample size calculations were based on an estimated 40% reduction in breast cancer mortality, which is greater than the typical reduction in mortality observed in the other six trials that included women in this age group. ³⁰

Subgroup analyses of the other trials that included women under 50 have yielded conflicting evidence regarding the benefit of screening women aged 40-49. No benefit was observed in the Stockholm trial or in one arm of the two-county trial, while the remaining trials reported nonsignificant benefits of about 22% or more. ^17,50 One meta-analysis, which pooled the results from 7-year follow-up of six published clinical trials without adjustment for variation in screening method or interval, found no reduction in breast cancer mortality for women in their forties (RR = 1.08 95% CI, 0.85 to 1.39). ⁴¹ When the Canadian trial was excluded from the analysis, the estimate changed little (RR= 0.99 95% CI, 0.74 to 1.32). The overview of the Swedish trials found a nonsignificant 13% reduction (RR= 0.87 95% CI, 0.63 to 1.20) only after 8-12 years of follow-up in this age group. ⁴⁰ More recent meta-analyses of published mammography trial data reported nonsignificant 8-10% reductions in breast cancer mortality in women aged 40-49. ^42,43 One meta-analysis reported a significant benefit for women in this age group when unpublished data were included and the Canadian trial was excluded. ⁴³ Longer duration of follow-up was associated with a greater reduction in mortality, although this finding may have been due to chance. ⁴² Thus, there is conflicting evidence from clinical trials and meta-analyses, primarily based on subgroup analyses, regarding the benefit of screening women aged 40-49. An ongoing British trial is evaluating the effectiveness of annual mammography screening in women enrolled at age 40 or 41.

A recent analysis of data by tumor size, nodal status, and stage from the BCDDP, a U.S. screening project using annual two-view mammography and CBE, suggests comparable 14-year survival rates for women 40-49 and women 50-59. ⁵¹ A similar analysis of breast cancers detected in the Swedish two-county trial confirms this finding. ⁵² Based on these data, time series comparisons of survival, frequency of interval cancers in the two-county trial, and subgroup analysis of available clinical trial data, some experts have suggested that annual screening intervals may be necessary to achieve a reduction in breast cancer mortality from screening for women aged 40-49. ^19,20,52 In a meta-analysis of published trial results, however, the estimated mortality reduction from screening women in this age group was similar for 12- and 18-33-month screening intervals (1% and 12%, respectively). ⁴²

There is no direct evidence that assesses the effectiveness of CBE alone compared to no screening. Modeling studies of the HIP trial estimated that two thirds of the effectiveness of the combined screening may have been a result of CBE. ^53-56 The Canadian NBSS 2 was designed to test the incremental value of annual mammography over a careful annual CBE among women aged 50-59 at study entry. ²⁴ At 7-year follow-up, there was no difference in breast cancer mortality for the group receiving combined screening compared to CBE alone (RR = 0.97 95% CI, 0.62 to 1.52). This result suggests that thorough CBE may be as effective as mammography for screening in this age group. The confidence interval is wide, however, and substantial benefit or harm from screening is not excluded by the preliminary data. Concerns regarding the early quality of mammography of Canadian NBSS 1 also apply to this trial. ⁴⁸ Long-term follow-up and additional studies are needed to confirm this apparent lack of an incremental benefit of mammography above a careful, thorough annual CBE. It is also unclear whether CBE adds benefit to screening with mammography. A meta-analysis of mammography trial results reported similar reductions in breast cancer mortality with and without the addition of CBE. ⁴²

Evidence for effectiveness of BSE alone is also limited. In the United Kingdom Trial of Early Detection of Breast Cancer, a nonrandomized community trial, 40-50% of women living in two districts participated in BSE instruction that included a short film and a lecture by a specially trained health provider. ⁵⁷ At 7-year follow-up, there was no reduction in breast cancer mortality in the BSE communities compared with the control districts. Baseline comparability of intervention and control districts, treatment variation by community, and contamination by other screening modalities were not assessed, however. A World Health Organization (WHO) population-based randomized controlled trial in Leningrad comparing formal BSE instruction to no intervention in women aged 40-64 has reported increases in physician visits, referrals for further screening tests, and excisional biopsies in the intervention group at 5-year follow-up. ⁵⁸ Breast cancer patients in the two groups did not differ in number, size, or nodal status of their tumors. Completeness of endpoint assessment is a concern in this study, given the lack of a national tumor registry. Follow-up through 1999 is planned for reporting mortality results. In a case-control study of women who had been diagnosed with advanced stage (TNM III or IV) breast cancer, there was no association between disease status and self-reported BSE. ⁵⁹ Proficiency in practicing BSE, however, was reported as poor by both cases and controls. For the small group of women reporting thorough BSE compared to all others, the relative risk was 0.54 (95% CI, 0.30 to 0.98). A meta-analysis of pooled data from 12 descriptive studies found that women who practiced BSE before their illness were less likely to have a tumor of 2.0 cm or more in diameter or to have evidence of extension to lymph nodes. ⁶⁰ The studies from which these data were obtained, however, suffer from important design limitations and provide little information on clinical outcome (i.e., breast cancer mortality). Retrospective studies of the effectiveness of BSE have produced mixed results. ^27,61-63

The American Cancer Society (ACS), ⁶⁴ American College of Radiology, ⁶⁵ American Medical Association, ⁶⁶ American College of Obstetricians and Gynecologists (ACOG), ⁶⁷ and a number of other organizations ⁶⁵ recommend screening with mammography every 1-2 years and annual CBE beginning at the age of 40, and annual mammography and CBE beginning at age 50.

The American Academy of Family Physicians (AAFP) recommends CBE every 1-3 years for women aged 30-39 and annually for those aged 40 and older, and mammography annually beginning at age 50 ⁶⁸ these recommendations are currently under review. The American College of Physicians (ACP) recommends screening mammography every 2 years for women aged 50-74 and recommends against mammograms for women under 50 or over 75 years and baseline mammograms. ⁶⁹ The ACP makes the same recommendations for high-risk women, unless the woman expresses great anxiety about breast cancer or insists on more intensive screening. The Canadian Task Force on the Periodic Health Examination recommends annual CBE and mammography for women aged 50-69 and recommends against mammograms in women under 50. ⁷⁰ The National Cancer Institute states there is a general consensus among experts that routine mammography and CBE every 1-2 years in women aged 50 and over can reduce breast cancer mortality, and that randomized clinical trials have not shown a statistically significant reduction in mortality for women under the age of 50. ⁷¹

Organizations that presently recommend routine teaching of BSE include the AAFP, ⁶⁸ ACOG, ⁶⁷ and ACS. ⁶⁴ The recommendations of the AAFP are currently under review.

At this time, there is little doubt that breast cancer screening by mammography with or without CBE has the potential of reducing mortality from breast cancer for women aged 50 through about 70. The benefit derived from biennial screening appears to be quite similar to the benefit derived from annual screening. Given this similarity in effectiveness, biennial screening is likely to have the added benefit of increased cost-effectiveness. The incremental value of CBE above mammography or vice versa is uncertain, although the Canadian NBSS 2 ²⁴ suggests that careful CBE may be as effective as mammography.

Evidence does not establish a clear benefit from screening in women aged 40-49. Only the Canadian NBSS 1 ³⁰ was designed to test the effectiveness of screening in this age group, however, and none of the trials had adequate power for subgroup analysis. If screening is in fact ineffective in younger women, one possible explanation is a lower sensitivity of mammography in younger women (see Accuracy of Screening Tests ). Other possibilities include suboptimal screening intervals, differential (less aggressive) treatment offered to women with mammographically detected cancer, and varying biologic characteristics of breast tumors. ^52,72 The Swedish overview, ⁴⁰ HIP, ³⁷ and Edinburgh ³⁶ trials suggest some benefit in women aged 40-49 after 8-12 years of follow-up, but it is possible that the delayed benefit is due to screening women in their fifties who entered the trials in their middle to late forties. ^72a The final results of the Canadian NBSS 1 may provide important information. An ongoing British trial and a proposed trial in Europe which will enroll women only in their early forties and compare mammography to no screening could also clarify this issue. ⁷³ Until further information is available, it is unclear whether any potential improvement in breast cancer mortality achieved by screening women aged 40-49 is of sufficient magnitude to justify the potential adverse effects that may occur as a result of widespread screening.

Because breast cancer incidence increases with age, the burden of suffering due to breast cancer in elderly women is substantial. In addition, there is no evidence (as there is in younger women) that sensitivity of mammography in older women is not comparable to that in women aged 50-69. This is an age group, moreover, in which underutilization of breast cancer screening is common. ^74-76 In a decision analysis of the utility of screening women over 65 for breast cancer, screening saved lives at all ages, but the savings decreased substantially with increasing age and comorbidities. ⁷⁷ In the oldest women, those aged >=85, short-term morbidity such as anxiety or discomfort from the screening may have outweighed the small benefits. Until more definitive data become available for elderly women, it is reasonable to concentrate the large effort and expense associated with screening mammography on women in the age group for which benefit has been most clearly demonstrated: those aged 50-69. Screening women aged 70 and older might be considered on an individual basis, depending on general health and other considerations (e.g., personal preference of the patient).

The age range of 50-69 years, for which mammography has been proven effective, is to a large extent based on artificial cutpoints chosen for study purposes rather than on biologic cutpoints above or below which the ratio of benefits to risks sharply decreases. Both the incidence of breast cancer and the sensitivity of mammography increase with age. Thus, it is logical that women in their seventies, for whom only limited clinical trial experience is available, benefit from breast cancer screening. For women aged <50 years, evidence has been insufficient to establish a clear benefit from breast cancer screening. This age cutpoint may be a marker for biologic changes that occur with age, especially menopause. It is therefore plausible that women in their late forties, particularly postmenopausal women, might derive some intermediate benefit from screening. The risks and benefits of mammography and CBE may be best considered as changing on an age continuum rather than at a specific chronologic age. Guidelines for breast cancer screening should be interpreted with this in mind.

No large study has quantitated the effectiveness of breast cancer screening by either CBE or mammography for women who are at higher risk of developing breast cancer than the general population. The increased incidence of disease in high-risk women increases the positive predictive value (PPV) of screening tests used in this group. For example, in a community screening program, the PPV of mammography was increased 2-3-fold for women with a family history of breast cancer. ³¹ This is an especially important consideration for women under 50, in whom the benefit of screening has not been established for the general population. There may be a benefit from screening younger women in high-risk groups, but studies confirming this effect are lacking. Nevertheless, given their increased burden of suffering, screening high-risk women under age 50 may be considered on an individual basis for women who express a strong preference for such screening.

Data regarding the effectiveness of BSE are extremely limited, and the accuracy of BSE as currently practiced appears to be considerably inferior to that of CBE and mammography. False-positive BSE, especially among younger women in whom breast cancer is uncommon, could lead to unnecessary anxiety and diagnostic evaluation, although a small randomized clinical trial ²⁹ did not find such adverse effects. A point also worth consideration is that time devoted to teaching BSE may reduce time available for prevention efforts with proven effectiveness. Given the present state of knowledge and the potential adverse effects and opportunity cost, a recommendation for or against inclusion of teaching BSE during the periodic health examination cannot be made.

CLINICAL INTERVENTION

Screening for breast cancer every 1-2 years, with mammography alone or mammography and annual clinical breast examination (CBE), is recommended for women aged 50-69 ("A" recommendation). Clinicians should refer patients to mammographers who use low-dose equipment and adhere to high standards of quality control. Such standards have recently been established by the Mammography Quality Standards Act, a federal law mandating that all mammography sites in the U.S. be accredited through a process approved by the Department of Health and Human Services. ⁷⁸ There is insufficient evidence to recommend annual CBE alone for women aged 50-69 ("C" recommendation). For women aged 40-49, there is conflicting evidence of fair to good quality regarding clinical benefit from mammography with or without CBE, and insufficient evidence regarding benefit from CBE alone therefore, recommendations for or against routine mammography or CBE cannot be made based on the current evidence ("C" recommendation). There is no evidence specifically evaluating mammography or CBE in high-risk women under age 50 recommendations for screening such women may be made on other grounds, including patient preference, high burden of suffering, and the higher PPV of screening, which would lead to fewer false positives than are likely to occur from screening women of average risk in this age group. There is limited and conflicting evidence regarding clinical benefit of mammography or CBE for women aged 70-74 and no evidence regarding benefit for women over age 75 however, recommendations for screening women aged 70 and over who have a reasonable life expectancy may be made based on other grounds, such as the high burden of suffering in this age group and the lack of evidence of differences in mammogram test characteristics in older women versus those aged 50-69 ("C" recommendation). There is insufficient evidence to recommend for or against teaching BSE in the periodic health examination ("C" recommendation).

The draft update of this chapter was prepared for the U.S. Preventive Services Task Force by Marisa Moore, MD, MPH, and Carolyn DiGuiseppi, MD, MPH.

Colorectal cancer is the second most common form of cancer in the U.S. and has the second highest mortality rate, accounting for about 140,000 new cases and about 55,000 deaths each year. ¹ An individual's lifetime risk of dying of colorectal cancer in the U.S. has been estimated to be 2.6%. ² About 60% of patients with colorectal cancer have regional or distant metastases at the time of diagnosis. ¹ Estimated 5-year survival is 91% in persons with localized disease, 60% in persons with regional spread, and only 6% in those with distant metastases. ² The average patient dying of colorectal cancer loses 13 years of life. ² In addition to the mortality associated with colorectal cancer, this disease and its treatment -- surgical resection, colostomies, chemotherapy, and radiotherapy -- can produce significant morbidity. Persons at highest risk of colorectal cancer include those with uncommon familial syndromes (i.e., hereditary polyposis and hereditary nonpolyposis colorectal cancer [HNPCC]) and persons with longstanding ulcerative colitis. ^3,4 Familial syndromes are estimated to account for 6% of all colorectal cancers, ³ and various genetic mutations associated with these syndromes have been identified. ^4a Other principal risk factors include a history of colorectal cancer or adenomas in a first-degree relative, a personal history of large adenomatous polyps or colorectal cancer, and a prior diagnosis of endometrial, ovarian, or breast cancer. In an analysis of two large cohorts involving over 840,000 patient-years of follow-up, a family history of colorectal cancer was associated with a significant increase in risk in younger persons (1.7-4-fold increase between ages 40 and 60), but was not associated with a significantly increased risk in persons after age 60 ^4b risk was higher in persons with more than one affected relative. The absolute increase in lifetime risk in persons with a family history was modest, however: an estimated cumulative incidence of colorectal cancer by age 65 of 4% vs. 3% in persons without a family history. ^4b Diets high in fat or low in fiber may also increase the risk of colorectal cancer. ³

The principal screening tests for detecting colorectal cancer in asymp-tomatic persons are the digital rectal examination, FOBT, and sigmoidoscopy. Less frequently mentioned screening tests include barium enema and colonoscopy, which have been advocated primarily for high-risk groups. The digital rectal examination is of limited value as a screening test for colorectal cancer. The examining finger, which is only 7-8 cm long, has limited access even to the rectal mucosa, which is 11 cm in length. A negative digital rectal examination provides little reassurance that the patient is free of colorectal cancer because fewer than 10% of colorectal cancers can be palpated by the examining finger. ³

A second screening maneuver is FOBT. The reported sensitivity and specificity of FOBT for detecting colorectal cancer in asymptomatic persons are 26-92% and 90-99%, respectively (usually based on two samples from three different stool specimens), with the widely varying estimates reflecting differences in study designs. ^5-10 Positive reactions on guaiac impregnated cards, the most common form of testing, can signal the presence of bleeding from premalignant adenomas and early-stage colorectal cancers. The guaiac test can also produce false-positive results, however. The ingestion of foods containing peroxidases, ¹¹ and gastric irritants such as salicylates and other antiinflammatory agents, ¹² can produce false-positive test results for neoplasia. Nonneoplastic conditions, such as hemorrhoids, diverticulosis, and peptic ulcers, can also cause gastrointestinal bleeding. FOBT can also miss small adenomas and colorectal malignancies that bleed intermittently or not at all. ^13,14 Other causes of false-negative results include heterogeneous distribution of blood in feces, ¹⁵ ascorbic acid and other antioxidants that interfere with test reagents, ¹⁶ and extended delay before testing stool samples. ¹⁷

As a result, when FOBT is performed on asymptomatic persons, the majority of positive reactions are falsely positive for neoplasia. The reported positive predictive value among asymptomatic persons over age 50 is only about 2-11% for carcinoma and 20-30% for adenomas. ^6,5,9,18-20 Assuming a false-positive rate of 1-4%, a person who receives annual FOBT from age 50 to age 75 has an estimated 45% probability of receiving a false-positive result. ²¹ This large proportion of false-positive results is an important concern because of the discomfort, cost, and occasional complications associated with follow-up diagnostic tests, such as barium enema and colonoscopy. ^22,23 Rehydration of stored slides can improve sensitivity, but this occurs at the expense of specificity. ²⁴ In one study, rehydration improved sensitivity from 81% to 92%, but it decreased specificity from 98% to 90% and lowered positive predictive value from 6% to 2%. Due to the high false-positive rate, about one third of the entire screened population of asymptomatic patients underwent colonoscopy for abnormal FOBT results within a 13-year period. ⁵

Other tests have been proposed to improve the accuracy of screening for fecal occult blood. Current evidence is equivocal as to whether HemoQuant (SmithKline Diagnostics, Sunnyvale, CA), a quantitative measurement of hemoglobin in the stool, has better sensitivity or specificity than does qualitative FOBT. ^9,10,25-29 Recently developed hemoglobin immunoassays offer the promise of improved sensitivity and specificity but require further evaluation before being considered for routine screening. ^30,31

The third screening test for colorectal cancer is sigmoidoscopy. Sigmoidoscopic screening in asymptomatic persons detects 1-4 cancers per 1,000 examinations. ^32,33 However, the sensitivity and diagnostic yield of sigmoidoscopy screening varies with the type of instrument: the rigid (25 cm) sigmoidoscope, the short (35 cm) flexible fiberoptic sigmoidoscope, or the long (60 cm) flexible fiberoptic sigmoidoscope. Since only 30% of colorectal cancers occur in the distal 20 cm of bowel, and less than half occur in or distal to the sigmoid colon, ^34-37 the length of the sigmoidoscope has a direct effect on case detection. The rigid sigmoidoscope, which has an average depth of insertion of about 20 cm ^38-44 and allows examination to just above the rectosigmoid junction, ⁴⁵ can detect only about 25-30% of colorectal cancers. The 35-cm flexible sigmoidoscope, however, can visualize about 50-75% of the sigmoid colon and can detect about 50-55% of polyps. Longer 60-cm instruments have an average depth of insertion of 40-50 cm, reaching the proximal end of the sigmoid colon in 80% of examinations ^46,47 with the capability of detecting 65-75% of polyps and 40-65% of colorectal cancers ^48-52 Researchers have examined the feasibility of introducing a 105-cm flexible sigmoidoscope in the family practice setting, ⁵³ but it is unclear whether the added length substantially increases the rate of detection of premalignant or malignant lesions. Barium enema studies have confirmed that some neoplasms within reach of the sigmoidoscope may not be seen on endoscopy. ⁵⁴

Sigmoidoscopy can also produce false-positive results, primarily by detecting polyps that are unlikely to become malignant during the patient's lifetime. Autopsy studies have shown that 10-33% of older adults have colonic polyps at death, ⁵⁵ but only 2-3% have colorectal cancer. ^56-58 Depending on the type of adenomatous polyp, an estimated 5-40% eventually become malignant, ⁵⁹ a process that takes an average of 10-15 years. ^60,61 It follows that the majority of asymptomatic persons with colonic polyps discovered on routine sigmoidoscopic examination will not develop clinically significant malignancy during their lifetime. For these persons, interventions that typically follow such a discovery (i.e., biopsy, polypectomy, frequent colonoscopy), procedures that are costly, anxiety provoking, and potentially harmful, are unlikely to be of significant clinical benefit.

Other potential screening tests for colorectal cancer include colonoscopy and barium enema, which appear to have comparable accuracy. About 95% of colorectal cancers are within reach of the colonoscope, and the examination has an estimated 75-95% sensitivity in detecting lesions within its reach. ^20,21 Colonoscopy, which requires sedation and often involves the use of a hospital suite, is more expensive than other screening tests and has a higher risk of anesthetic and procedural complications. The estimated sensitivity and specificity of air-contrast barium enema in detecting lesions within its reach are about 80-95% and 90%, respectively, using subsequent diagnosis as a reference standard. ²¹ Some retrospective studies have reported a higher sensitivity of barium enema for detecting colorectal cancer (about 90-96%), ^62,63 with pathologic diagnosis as the reference standard, but these estimates generally do not account for the selection bias introduced by the case-selection methods.

Persons with early-stage colorectal cancer at the time of diagnosis appear to have longer survival than do persons with advanced disease. ² Since there is little information on the extent to which lead-time and length biases (see Chapter ii) account for these differences, researchers in the U.S. and Europe launched large clinical trials in the late 1970s to collect prospective data on the effects of screening on co-lorectal cancer mortality.

Two of these trials ^5,6 examined the effect of routine FOBT on colorectal cancer mortality. A randomized controlled trial involving over 46,000 volunteers over age 50 found that the 13-year cumulative mortality from colorectal cancer was 33% lower among persons advised to undergo annual FOBT (5.9 deaths per 1,000) than among a control group that was not offered screening (8.8 deaths per 1,000). ⁵ The report provided insufficient data, however, to determine to what extent observed differences in outcome were attributable to FOBT or to the large number of colonoscopies that were performed due to frequent false-positive FOBT. An analysis of the study data by other authors suggested that one third to one half of the mortality reduction was due to "chance" selection of persons for colonoscopy, ⁶⁴ but the assumptions in the analysis have been disputed by the authors. ⁶⁵ Another controlled trial, ⁶ which was not randomized, assigned over 21,000 patients to a control group that received a standard periodic health examination or to a study group that was also offered FOBT both groups received sigmoidoscopy screening. Among new patients (first visit to the preventive medicine clinic), colorectal cancer mortality was 43% lower in the study group than in controls, a difference of borderline statistical significance (p = 0.053, one-tail), and there was no difference in outcomes among patients seen previously at the clinic. Recent case-control studies have also reported a 31-57% reduction in risk among persons receiving FOBT. ^66,67 Three large clinical trials of FOBT screening, currently under way in Europe, are expected to report their results in the coming years. ^7,68,69

Recent case-control studies have provided important information on the effectiveness of sigmoidoscopy screening. The largest study found that 9% of persons who died of colorectal cancer occurring within 20 cm of the anus had previously undergone a rigid sigmoidoscopic examination, whereas 24% of persons in the control group had received the test. ⁷⁰ The adjusted odds ratio of 0.41 (95% confidence interval, 0.25-0.69) suggested that sigmoidoscopy screening reduced the risk of death by 59% for cancers within reach of the sigmoidoscope. The investigators noted that the adjusted odds ratio for patients who died of more proximal colon cancers was 0.96. This finding added support to the hypothesis that the reduced risk of death from cancers within reach of the rigid sigmoidoscope was due to screening rather than to confounding factors. Another case-control study reported that the odds ratio for dying of colorectal cancer was 0.21 in screened subjects, and the benefit appeared to be limited to cancers within the reach of the sigmoidoscope. ⁷¹

Older evidence of the effectiveness of sigmoidoscopy screening suffered from important design limitations. A randomized controlled trial of multiphasic health examinations, which included rigid sigmoidoscopy, reported that the study group had significantly lower incidence and mortality rates from colorectal cancer. ^72-74 A subsequent analysis of the data, however, revealed that the proportion of subjects receiving sigmoidoscopy and the rate of detection or removal of polyps were similar in both the study and control groups, thus suggesting little benefit from sigmoidoscopy. ⁷⁵ Two large screening programs found that persons receiving periodic rigid sigmoidoscopy had less advanced disease and better survival from colon cancer than was typical of the general population. ^76-78 However, both studies lacked internal controls and used nonrandomized methods to select participants other methodologic problems with these investigations are outlined in other reviews. ^75,79

An important consideration in assessing the effectiveness of sigmoidoscopic screening is the potential iatrogenic risk associated with the procedure. Complications from sigmoidoscopy are relatively rare in asymptomatic persons but can be potentially serious. Perforations are reported to occur in approximately 1 of 1,000-10,000 rigid sigmoidoscopic examinations. ^20,21,32,80 Although there are fewer data available on flexible sigmoidoscopy, the complication rate appears to be less than or equal to that observed for rigid sigmoidoscopy. The reported risk of perforation from colonoscopy is about one in 500-3,000 examinations, ^5,81 and the risk of serious bleeding is 1 in 1,000. ⁵ The estimated risk of perforation during barium enema is 1 in 5,000-10,000 examinations. ⁸²

There is little useful evidence regarding the effectiveness of colonoscopy or barium enema screening in asymptomatic persons. Several recent studies describe colonoscopy screening of asymptomatic persons, but they report only the anatomic distribution of polyps and do not address clinical outcomes. ^48,49,83 A prospective study demonstrated a significantly lower incidence of subsequent colorectal cancer in patients with previously diagnosed adenomas who received periodic colonoscopy and polypectomy, but potential biases in the control groups (historical controls and population incidence rates) prevent definitive conclusions. ⁸⁴ No studies have directly examined the effectiveness of routine barium enema screening in decreasing colorectal cancer mortality in asymptomatic persons. Modeling studies suggest its effectiveness might be comparable to a screening strategy of periodic sigmoidoscopy. ²¹

There is limited information on the optimal age to begin or end screening and the frequency with which it should be performed. The age groups in which screening has been shown to decrease mortality are ages 50-80 for FOBT ⁵ and over age 45 for sigmoidoscopy. ⁷⁰ Theoretically, the potential yield from screening should increase beyond age 50 since the incidence of colorectal cancer after this age doubles every 7 years. ² Modeling studies suggest that beginning screening at age 40 rather than at age 50 offers no improvement in life expectancy. ²¹ There is little evidence from which to determine the proper age for discontinuing screening. The optimal interval for screening is less certain for sigmoidoscopy than for FOBT, for which there is good evidence of benefit from annual screening. A modeling study of sigmoidoscopy screening estimated that an interval of 10 years would preserve 90% of the effectiveness of annual screening this model assumes that adenomatous polyps take 10-14 years to become invasive cancers. ²¹ Another model suggested that an interval of 2-4 years would allow detection of 95% of all polyps greater than 13 mm in diameter. ⁸⁵ In a case-control study, the risk reduction associated with sigmoidoscopy screening did not diminish during the first 9-10 years after sigmoidoscopy. ⁷⁰ Other studies suggest that a single sigmoidoscopic screening examination may be adequate for low-risk individuals, ⁸⁶ an approach being investigated in the United Kingdom. ⁸⁷

Primary preventive measures to prevent colorectal cancer are currently under investigation. An association between colorectal cancer and dietary intake of fat and fiber has been demonstrated in a series of epidemiologic studies (see Chapter 56). Case-control and cohort studies also suggest that aspirin use may decrease the risk of colon cancer. ^88-90

The American Cancer Society recommends annual digital rectal examination for all adults beginning at age 40, annual FOBT beginning at age 50, and sigmoidoscopy every 3-5 years beginning at age 50. ⁹¹ Similar recommendations have been issued by the American Gastroenterological Association, ⁹² the American Society for Gastrointestinal Endoscopy, ⁹² and the American College of Obstetricians and Gynecologists. ⁹³ The American College of Physicians' (ACP) guidelines, revised in 1995, recommend offering a variety of screening options to persons from age 50 to 70, depending on local resources and patient preferences: flexible sigmoidoscopy, colonoscopy, or air-contrast barium enema, repeated at 10-year intervals. The ACP recommends that annual FOBT be offered to persons who decline these screening tests, but concluded that there was relatively little benefit of continuing endoscopic screening beyond age 70 in individuals who had been adequately screened up to that age. ²¹ The American College of Radiology recommends screening with barium enema every 3-5 years as an equivalent alternative to periodic sigmoidoscopy. ⁹⁴ The recommendations of the American Academy of Family Physicians are currently under review. ⁹⁵ Most organizations recommend more intensive screening of those in high-risk groups (e.g., familial polyposis, inflammatory bowel disease) with periodic colonoscopy or barium enema. The Canadian Task Force on the Periodic Health Examination concluded that there was insufficient evidence to support screening of asymptomatic individuals over age 40 but that persons with a history of cancer family syndrome should be screened with colonoscopy. ⁹⁶ An expert panel convened by the Agency for Health Care Policy and Research is expected to issue guidelines for colorectal cancer screening and surveillance in 1996.

In summary, recent studies have provided compelling evidence of the effectiveness of FOBT and sigmoidoscopy screening, but the evidence is not definitive. At least one randomized controlled trial and several observational studies have shown that annual FOBT in persons over age 50 can reduce colorectal cancer mortality. This evidence does not, however, clarify whether the observed benefits were due to FOBT or to the effect of performing colonoscopy on a large proportion of the screened population. For sigmoidoscopy, a case-control study supports a strong association between regular screening and reduced colorectal cancer mortality from cancers within reach of the sigmoidoscope. This study was limited, however, by its small number of cases, potential selection biases, and inability to provide prospective evidence of benefit. There are additional concerns about the adverse effects, costs, and optimal frequency of screening. Studies that will help resolve these uncertainties are currently in progress the final results of ongoing European FOBT trials will be unavailable for several years, however, and a large United States study ⁹⁷ of FOBT and sigmoidoscopy screening will not be completed until the turn of the century.

An important limitation to the effectiveness of screening for colorectal cancer is the ability of patients and clinicians to comply with testing. Patients may not comply with FOBT for a variety of reasons, ^68,98 but compliance rates are generally higher than for sigmoidoscopy. Recent clinical trials report compliance rates of 50-80% for FOBT among volunteers, ^5-7,68,69 but lower rates (about 15-30%) have been reported in community screening programs. ^99-101 Although the introduction of flexible fiberoptic instruments has made sigmoidoscopy more acceptable to patients, ¹⁰² the procedure remains uncomfortable, embarrassing, and expensive, and therefore many patients may be reluctant to agree to this test. A survey of patients over age 50 found that only 13% wanted to receive a sigmoidoscopy examination after being advised that they should receive the test the most common reasons cited for declining the test were cost (31%), discomfort (12%), and fear (9%). ¹⁰³ In a study in which sigmoid-oscopy was recommended repeatedly, only 31% of participants consented to the procedure, ^72-74 but this study was performed during years when rigid sigmoidoscopy was common. Compliance rates as low as 6-12% have been reported. Studies suggest that physician motivation is a major determinant of patient compliance, ^104,105 and physicians may be reluctant to perform screening sigmoidoscopy on asymptomatic persons. It has been estimated that a typical family physician with 3,000 active patients (one third aged 50 or older) would have to perform five sigmoidoscopies daily to initially screen the population and two daily procedures for subsequent screening. ³³ In addition, examinations using 60-cm sigmoidoscopes are more time-consuming ^35-39 and require more extensive training ^106-108 than do those using shorter instruments.

Another limitation to screening is its cost. Although a formal cost-effectiveness analysis of screening for colorectal cancer is beyond the scope of this chapter, the economic implications associated with the widespread performance of FOBT and sigmoidoscopy are clearly significant. A single flexible sigmoidoscopic examination costs between $100 and $200. ^22,109 A policy of routine FOBT and sigmoidoscopic screening of all persons in the United States over age 50 (about 63 million persons) would cost over $1 billion per year in direct charges. ¹⁰⁹ Others have calculated that FOBT screening alone could cost the United States and Canada between $500 million and $1.2 billion each year. ^110,111 Another model predicted that performing annual FOBT on persons over age 65 would cost about $35,000 per year of life saved adding flexible sigmoidoscopy would increase the cost to about $42,000 to $45,000 per year of life saved. ¹¹² Mathematical models suggest that barium enema screening every 3-5 years might have comparable or superior cost-effectiveness when compared with sigmoidoscopy screening, but neither the clinical effectiveness nor acceptability of barium enema screening has been demonstrated directly in clinical studies.

The downstream effects of screening are also of concern. The logistical difficulties and costs of performing FOBT and sigmoidoscopy on a large proportion of the U.S. population are significant, due to the limited acceptability of the tests and the expense of performing screening and follow-up on a large proportion of the population. Moreover, the tests have potential adverse effects that must be considered, such as false-positive results that lead to expensive and potentially harmful diagnostic procedures. Studies that have reported reduced mortality from FOBT used rehydrated slides to increase sensitivity, thereby producing a higher proportion of false-positive results than with nonrehydrated slides 32% of the annually screened population underwent colonoscopy during a 13-year follow-up period. ⁶⁵ If this rate is extrapolated to the 63 million Americans over age 50 who would receive annual FOBT, it can be predicted that about 20 million persons would require colonoscopy.

The full implications of this "screening cascade" need to be considered, along with the scientific evidence of clinical benefits, before reaching conclusions about appropriate public policy. For example, using nonrehydrated slides rather than rehydrated slides could substantially reduce the adverse effects and costs of a national screening program. As noted earlier, data from a major screening trial suggest that using nonrehydrated slides rather than rehydrated slides could increase the positive predictive value of FOBT from 2% to 6%, subjecting far fewer screened persons to unnecessary colonoscopy. This improvement in specificity, however, comes at the expense of sensitivity, which decreased from 92% with rehydration to 81% in nonrehydrated slides. The use of nonrehydrated slides would therefore allow a much larger proportion of persons with cancer to escape detection.

The special considerations that apply to persons at increased risk of colorectal cancer are complicated by inadequate epidemiologic and effectiveness data and inconsistent disease classifications. Having a single family member with colorectal cancer does not carry the high risk associated with hereditary cancer syndromes (e.g., familial polyposis, HNPCC). ^4,113 A family history that is suggestive of the latter includes a pattern of diagnoses consistent with autosomal dominant inheritance of a highly penetrant disorder. Characteristic features include a family history of colorectal cancer being diagnosed at an early age, frequent cases of multiple primary cancers, or florid adenomatous colonic polyps. Performing periodic colonoscopy to screen for cancer in these groups may be justified in light of the high risk of disease and the incidence of proximal colonic lesions, but there is no direct evidence to determine the optimal strategy in this population.

CLINICAL INTERVENTION

Screening for colorectal cancer is recommended for all persons aged 50 or over ("B" recommendation). Effective methods include FOBT and sigmoidoscopy. There is insufficient evidence to determine which of these screening methods is preferable or whether the combination of FOBT and sigmoidoscopy produces greater benefits than either test alone. Although there is good evidence to support FOBT on an annual basis, there is insufficient evidence to recommend a periodicity for sigmoidoscopy screening. A frequency of every 3-5 years has been recommended by other groups on the basis of expert opinion, and a well-designed case-control study suggests that protection remains unchanged for at least 10 years after rigid sigmoid-oscopy. Current evidence suggests that at least some of the benefits of FOBT in reducing colorectal cancer mortality may be achieved through colonoscopic evaluation of abnormal results. Widespread FOBT or sigmoidoscopy screening is therefore likely to generate substantial direct and indirect costs. Appropriate public policy may require consideration of factors other than the scientific evidence of clinical benefit. The appropriate age to discontinue screening has not been determined.

Patients who are offered these tests should receive information about the potential benefits and harms of the procedures, the probability of false-positive results, and the nature of the tests that will be performed if an abnormality is detected. FOBT screening should adhere to current guidelines for dietary restrictions, sample collection, and storage. Although slide rehydration increases the sensitivity of FOBT, it also decreases specificity, and there is insufficient evidence to determine whether rehydration results in better outcomes than screening with nonrehydrated slides. Sigmoidoscopy should be performed by a trained examiner. The instrument should be selected on the basis of examiner expertise and patient comfort. Longer (e.g., 60-cm instrument) flexible sigmoidoscopes have greater sensitivity and are more comfortable than shorter, rigid sigmoidoscopes.

There is insufficient evidence to recommend for or against routine screening with digital rectal examination, barium enema, or colonoscopy ("C" recommendation). Recommendations against using these tests for screening average-risk persons may be made on other grounds (e.g., availability of alternate tests of proven effectiveness, inaccuracy of digital rectal examination, costs and risks of colonoscopy).

In persons with a single first-degree relative with colon cancer, it is not clear that the modest increase in the absolute risk of cancer justifies routine use of colonoscopy over other screening methods. The increased risk of developing cancer at younger ages may justify beginning screening before age 50 in persons with a positive family history, however, especially when affected relatives developed colorectal cancer at younger ages. Direct evidence of the benefit of screening in younger persons is not available for any group. For persons with a family history of hereditary syndromes associated with a very high risk of colon cancer (i.e., familial polyposis or HNPCC), as well as those previously diagnosed with ulcerative colitis, high-risk adenomatous polyps, or colon cancer, regular endoscopic screening is part of routine diagnosis and management referral to specialists is appropriate for these high-risk patients.

The draft update of this chapter was prepared for the U.S. Preventive Services Task Force by Steven H. Woolf, MD, MPH.

Approximately 16,000 new cases of cervical cancer are diagnosed each year, and about 4,800 women die from this disease annually. ¹ The lifetime risk of dying from cervical cancer in the U.S. is 0.3%. ^1a Although the 5-year survival rate is about 90% for persons with localized cervical cancer, it is considerably lower (about 14%) for persons with advanced (Stage IV) disease. The incidence of invasive cervical cancer has decreased significantly over the last 40 years, due in large part to organized early detection programs. Although all sexually active women are at risk for cervical cancer, the disease is more common among women of low socioeconomic status, those with a history of multiple sex partners or early onset of sexual intercourse, and smokers. The incidence of invasive cervical cancer among young white women has increased recently in the United States. Infection with human immunodeficiency virus (HIV) and certain types of human papilloma virus (HPV) also increases the risk of cervical cancer. ²

The principal screening test for cervical cancer is the Pap smear. Although the Pap smear can sometimes detect endometrial, vaginal, and other cancers, ^3,4 its use as a screening test is intended for the early detection of cervical dysplasia and cancer. Other proposed cervical screening tests include cervicography, colposcopy, and testing for HPV infection. The role of pelvic examination, which usually accompanies the collection of the cervical specimen, is discussed in Chapter 14 in relation to ovarian cancer screening.

Precise data on the sensitivity and specificity of the Pap smear in detecting cancer and dysplasia are lacking due to methodologic problems. Depending on study design, false-negative rates of 1-80% have been reported a range of 20-45% has been quoted most frequently, primarily in studies comparing normal test results with subsequent smears. ^5-11 Studies using cone biopsy results as the reference standard have reported false-negative rates as low as 10%. ¹² Although reliable data are lacking, specificity is probably greater than 90% ¹³ and may be as high as 99%. ^6,11 The detection of precursor cervical intraepithelial neoplasia (CIN) by Pap smears may have poor specificity for cervical carcinoma, however, because a substantial proportion of CIN-1 lesions do not progress to invasive disease or may regress spontaneously. The test-retest reliability of Pap smears is influenced to some extent by variations in the expertise and procedures of different cytopathology laboratories.

A large proportion of diagnostic errors may be attributable to laboratory error. In one study of over 300 laboratories given slides with known cytologic diagnoses, false-negative diagnoses were made in 7.5% of smears with moderate dysplasia or frank malignancy, and false-positive diagnoses were made in 8.9% of smears with no more than benign atypia. ¹⁴ A survey of 73 laboratories in one state revealed a false-negative rate of 4.4% and a false-positive rate of 2.7%. ¹⁵ These data were reported in 1990, before the introduction of federal legislation designed to improve the accuracy of cytopathologic laboratory interpretation. ¹⁶ With the adoption of the Bethesda system for classification of cervical diagnoses, ¹⁷ a large proportion of benign smears are interpreted as "atypical," a finding that poses little premalignant potential but that often generates intensive follow-up testing.

Another cause of false-negative Pap smears is poor specimen collection technique. A 1991 survey of 600 laboratories found that 1-5% of specimens received were either unsatisfactory or suboptimal, generally because endocervical cells were absent from the smear. ¹⁸ Another study found that poor sampling technique accounted for 64% of false-negative results. ¹⁹ The Pap smear has traditionally been obtained with a spatula, to sample the ectocervix, and a cotton swab, to obtain endocervical cells. A 1990 survey found that about half of physicians used a spatula and cotton swab to collect Pap smears. ²⁰ In recent years, new devices have been introduced to improve sampling of the squamocolumnar junction. Controlled studies have shown that using an endocervical brush in combination with a spatula is more likely to collect endocervical cells than using a spatula or cotton swab. ^21-30 There is conflicting evidence, however, that the endocervical brush increases the detection rate for abnormal smears or affects clinical outcomes. ^31-33 There is also conflicting evidence regarding the importance of collecting endocervical cells. Although some large series have reported that CIN is detected over 2 times more frequently when endocervical cells are present, ^34,35 other series ^36,37 have shown no association between the presence of endocervical cells and the detection rate for dysplasia. The brush is more expensive than the cotton swab, but studies suggest that this cost is easily recovered by the reduced need for repeat testing. ³⁸ Other methods for improving the sensitivity of cervical cancer screening, such as acetic acid washes to improve the visibility of lesions, remain investigational. ^39,40

There are important potential adverse effects associated with inaccurate interpretation of Pap smears. False-negative results are significant because CIN or more invasive lesions may escape detection and progress to more advanced disease during the period between tests. The potential adverse effects of false-positive results include patient anxiety regarding the risk of cervical cancer, ^41,42 as well as the unnecessary inconvenience, discomfort, and expense of follow-up diagnostic procedures. Studies have shown that the distribution of patient education materials that explain the meaning of abnormal results is associated with a reduction in patient anxiety and stress and a better patient understanding of test results. ^43-45

Other tests, such as cervicography and colposcopy, have been proposed to help improve the sensitivity of screening, ⁴⁶ but their accuracy and technical requirements are suboptimal. Cervicography, in which a photograph of the cervix is examined for atypical lesions, has a sensitivity that is comparable to the Pap smear (approximately 60%) but a much lower specificity (approximately 50%) the reported positive predictive value in most studies is only 1-26%, and about 10-15% of cervigrams are unsatisfactory. ^47-51 Colposcopy, in which the cervix is examined under magnification with acetic acid washing and suspicious lesions are biopsied, is widely performed on women with abnormal Pap smears but has poor sensitivity (34-43%), specificity (68%), and positive predictive value (4-13%) when used as a screening test for cervical neoplasia in asymptomatic women. ^52-54 Other disadvantages of colposcopy screening include its cost, the limited availability of the equipment, the time and skills required to perform the procedure, and patient discomfort. Using a 10-point score for assessing pain, one study reported that women who underwent colposcopy gave the procedure a range of scores from 3 to 4.6. ⁵⁵

Another proposed screening strategy is testing for HPV infection, a known risk factor for cervical cancer. Of the more than 70 types of HPV that have been identified, several oncogenic forms (e.g., types 16 and 18) have a strong epidemiologic association with cervical cancer. However, the natural history of how HPV infection progresses to cancer is poorly understood. ⁵⁶ One study of women infected with either HPV type 16 or 18 found that 67% of the lesions remained unchanged or regressed after a mean of 5 years, 29% progressed to a more advanced stage of dysplasia, and 3% recurred. ⁵⁷ The high prevalence of HPV infection in young women also limits its predictive value. In one study, nearly half of female college students had evidence of HPV when tested by polymerase chain reaction technology. ⁵⁸ The reported positive predictive value of this HPV test for CIN-2 or CIN-3 lesions and carcinoma is less than 10%. ⁵⁹ HPV typing to identify women with oncogenic strains may improve the future accuracy of the test and its role in directing follow-up, but its current suitability for routine screening in asymptomatic women is limited by its poor predictive value, uncertain natural history, and, due to the absence of an effective treatment, the lack of evidence that screening affects clinical outcomes. ⁶⁰

Early detection of cervical neoplasia provides an opportunity to prevent or delay progression to invasive cancer by performing clinical interventions such as colposcopy, conization, cryocautery, laser vaporization, loop electrosurgical excision, and, when necessary, hysterectomy. ⁶¹ There is evidence that early detection through routine Pap testing and treatment of precursor CIN can lower mortality from cervical cancer. Correlational studies in the United States, Canada, and several European countries comparing cervical cancer data over time have shown dramatic reductions in the incidence of invasive disease and a 20-60% reduction in cervical cancer mortality rates following the implementation of cervical screening programs. ^62-70 Case-control studies have shown a strong negative association between screening and invasive disease, also suggesting that screening is protective. ^71-75 These observational studies do not constitute direct evidence that screening was responsible for the findings, ⁷⁶ and randomized controlled trials to provide such evidence have not been performed. Nonetheless, the large body of supportive evidence accumulated to date has prompted the adoption of routine cervical cancer screening in many countries and makes performance of a controlled trial of Pap smears unlikely for ethical reasons.

Observational data suggest that the effectiveness of cervical cancer screening increases when Pap testing is performed more frequently. ⁷² Aggressive dysplastic and premalignant lesions are less likely to escape detection when the interval between smears is short. There are, however, diminishing returns as frequency is increased. ^71,77 Although studies have shown that reducing the interval between Pap smears from 10 years to 5 years is likely to achieve a significant reduction in the risk of invasive cervical cancer, case-control studies and mathematical modeling have demonstrated that increasing to a 2-3-year interval offers only slight added benefit. ^71,78-80 There is little evidence that women who receive annual screening are at significantly lower risk for invasive cervical cancer than are women who are tested every 3-5 years. These findings were confirmed in a major study of eight cervical cancer screening programs in Europe and Canada involving over 1.8 million women. ⁸¹ According to this report, the cumulative incidence of invasive cervical cancer was reduced 64.1% when the interval between Pap tests was 10 years, 83.6% at 5 years, 90.8% at 3 years, 92.5% at 2 years, and 93.5% at 1 year. These estimates were for women aged 35-64 who had at least one screening before age 35, and they are based on the assumption of 100% compliance.

A consensus recommendation that all women who are or have been sexually active, or who have reached age 18, should have annual Pap smears has been adopted by the American Cancer Society, National Cancer Institute, American College of Obstetricians and Gynecologists (ACOG), American Medical Association, American Academy of Family Physicians (AAFP), and others. ⁸² The recommendation permits Pap testing less frequently after three or more annual smears have been normal, at the discretion of the physician. Guidelines for determining frequency based on risk factors have been issued by ACOG. ⁸³ The consensus did not recommend an age to discontinue Pap testing. The AAFP recommends that screening can be discontinued at age 65 if there is documented evidence of previously negative smears, but its recommendations are currently under review. ⁸⁴ The American College of Physicians (ACP) recommends Pap smears every 3 years for women aged 20-65, and every 2 years for women at high risk. ⁸⁵ The ACP also recommends screening women aged 66-75 every 3 years if not screened in the 10 years before age 66. The Canadian Task Force on the Periodic Health Examination recommends screening for cervical cancer with annual Pap smears in women following initiation of sexual activity or age 18, and after two normal smears, screening every 3 years to age 69. ⁸⁶ The Canadian Task Force recommends considering more frequent screening for women at increased risk. In their guidelines for adolescent preventive services (GAPS), the American Medical Association recommends annual screening with a Pap test for female adolescents who are sexually active or age 18 or older. ⁸⁷ Bright Futures also recommends annual Pap testing for sexually active adolescent females. ⁸⁸ Similar recommendations have been endorsed by the American Academy of Pediatrics. ⁸⁹

It has been estimated that screening women aged 20-64 every 3 years with Pap testing reduces cumulative incidence of invasive cervical cancer by 91%, requires about 15 tests per woman, and yields 96 cases for every 100,000 Pap smears. Annual screening reduces incidence by 93%, but requires 45 tests and yields only 33 cases for every 100,000 tests. ⁸¹ Empirical data also support the effectiveness of a 3-year interval. A study of 25,000 Dutch women found that screening a stable population every 3 years reduced the incidence of squamous cell carcinoma of the cervix from 0.38 per 1000 to zero within 12 years. ⁶⁷ There are, in addition, important economic considerations to performing Pap tests every 2-3 years, since annual testing could double or triple the total number of smears taken on over 92 million American women at risk, ⁹⁰ yet provide only limited added benefit in lowering mortality. ⁸¹

Annual testing, however, has been common. In the mid-1980s, a survey of recently trained gynecologists found that 97% recommend a Pap test at least once a year. ⁹¹ The preference of many clinicians for performing annual Pap smears is based on concerns that less frequent testing may result in more harm than good, but reliable scientific data to support these opinions are lacking. Specifically, advocates of annual testing have expressed concerns that data demonstrating little added value to annual testing are based on retrospective studies and mathematical models that are subject to biases and invalid assumptions that an interval longer than 1 year may permit aggressive, rapidly growing cancers to escape early detection that the public may obtain Pap smears at a lower frequency than that publicized in recommendations that a longer interval might affect compliance among high-risk women, a group with poor coverage even with an annual testing policy that repeated testing may offset the false-negative rate of the Pap smear that the test is inexpensive and safe and that a large proportion of women believe it is important to have an annual Pap test and, while visiting the clinician, may receive other preventive interventions. Definitive evidence to support these concerns is lacking.

Women who have never engaged in sexual intercourse are not at risk for cervical cancer and therefore do not require screening. ^92-94 In addition, screening of women who have only recently become sexually active (e.g., adolescents) is likely to have low yield. The incidence of invasive cancer in women under age 25 is only about 1-3 per 100,000, a rate that is much lower than that of older age groups. ¹¹ One study found that most women with CIN who had become sexually active at age 18 were not diagnosed with severe dysplasia or carcinoma in situ until age 30. ⁹³

Although invasive cervical cancer is uncommon at young ages, authorities have recommended since the early 1980s that screening should begin with the onset of sexual activity. ^82,92,94 This policy is based in part on the concern that a proportion of young women with CIN may have an aggressive cell type that can progress rapidly and go undetected if screening is delayed to a later age. There is some evidence that adenocarcinomas are accounting for a growing proportion of new cervical cancer cases in young women, ^95,96 but the exact incidence and natural history of aggressive disease in young women remain uncertain. The Pap smear is also a poor screening test for adenocarcinoma, compared with squamous cell carcinoma. Another reason given for early screening is the concern that the incidence of cervical dysplasia occurring in young women appears to be on the rise, coincident with the increasing sexual activity of adolescents. On these grounds, testing should begin by age 18, since many American teenagers are sexually active by this age. Screening in the absence of a history of sexual intercourse may be justified if the credibility of the sexual history is in question.

When screening is initiated, it is frequently recommended that the first two to three smears be obtained 1 year apart as a means of detecting aggressive tumors at a young age. There is little evidence to suggest, however, that young women whose first two tests are separated by 2 or 3 years, rather than 1 year, have a greater mortality or person-years of life lost. ⁷⁸ Recommendations to perform these first tests annually are based primarily on expert opinion.

Elderly women do not appear to benefit from Pap testing if repeated cervical smears have consistently been normal. ^97,78 Modeling data suggest that continued testing of previously screened women reduces the risk of dying from cervical cancer by only 0.18% at age 65 and 0.06% at age 74. ⁸⁰ Many older women have had incomplete screening, however. A reported 17% of women over age 65 and 32% of poor women in this age group have never received a Pap test. ⁹⁸ In a study of elderly minority women with an average age of 75 years, the mean reported number of prior Pap smears received since age 65 was 1.7. ⁹⁹ Further screening in this group of older women is important ^78,100 and some studies suggest that it is cost-effective. ¹⁰¹ Women who have undergone a hysterectomy in which the cervix was removed do not benefit from Pap testing, unless it was performed because of cervical cancer. Post-hysterectomy screening has the potential to detect vaginal cancer, but the yield and predictive value are likely to be very low. Women who had hysterectomies performed in which the cervix was left behind probably still require screening.

The effectiveness of cervical cancer screening is more likely to be improved by extending testing to women who are not currently being screened and by improving the accuracy of Pap smears than by efforts to increase the frequency of testing. Studies suggest that those at greatest risk for cervical cancer are the very women least likely to have access to testing. ^102,103 Incomplete Pap testing is most common among blacks, the poor, uninsured persons, the elderly, and persons living in rural areas. ^98,104-106 In addition, many women who are tested receive inaccurate results due to interpretative or reporting errors by cytopathology laboratories or specimen collection errors by clinicians. The failure of some physicians to provide adequate follow-up for abnormal Pap smears is another source of delay in the management of cervical dysplasia. ¹⁰⁷ Finally, a large proportion of patients with abnormal smears (30% in studies of poor, elderly black women ¹⁰⁸ ) do not return for further evaluation. Various techniques may enhance physician and patient compliance with screening, follow-up of abnormal results, and patient compliance with rescreening. ^109-112

CLINICAL INTERVENTION

Regular Pap tests are recommended for all women who are or have been sexually active and who have a cervix ("A" recommendation). Testing should begin at the age when the woman first engages in sexual intercourse. Adolescents whose sexual history is thought to be unreliable should be presumed to be sexually active at age 18. There is little evidence that annual screening achieves better outcomes than screening every 3 years. Pap tests should be performed at least every 3 years ("B" recommendation). The interval for each patient should be recommended by the physician based on risk factors (e.g., early onset of sexual intercourse, a history of multiple sex partners, low socioeconomic status). (Women infected with human immunodeficiency virus require more frequent screening according to established guidelines. ¹¹³ ) There is insufficient evidence to recommend for or against an upper age limit for Pap testing, but recommendations can be made on other grounds to discontinue regular testing after age 65 in women who have had regular previous screening in which the smears have been consistently normal ("C" recommendation). Women who have undergone a hysterectomy in which the cervix was removed do not require Pap testing, unless the hysterectomy was performed because of cervical cancer or its precursors. Patients at increased risk because of unprotected sexual activity or multiple sex partners should receive appropriate counseling about sexual practices (see Chapter 62).

The use of an endocervical brush increases the likelihood of obtaining endocervical cells, but there is conflicting evidence that sampling these cells improves sensitivity in detecting cervical neoplasia. Physicians should submit specimens to laboratories that have adequate quality control measures to ensure optimal accuracy in the interpretation and reporting of results. Thorough follow-up of test results should also be ensured, including repeat testing and referral for colposcopy as indicated. Physicians should consider providing patients with a pamphlet or other written information about the meaning of abnormal smears to help ensure follow-up and minimize anxiety over false-positive results.

There is insufficient evidence to recommend for or against routine cervicography or colposcopy screening for cervical cancer in asymptomatic women, nor is there evidence to support routine screening for HPV infection ("C" recommendation). Recommendations against such screening can be made on other grounds, including poor specificity and costs.

The draft update of this chapter was prepared for the U.S. Preventive Services Task Force by Steven H. Woolf, MD, MPH.

Prostate cancer is the most common noncutaneous cancer in American men. ¹ After lung cancer, it accounts for more cancer deaths in men than any other single cancer site. Prostate cancer accounted for an estimated 244,000 new cases and 40,400 deaths in the U.S. in 1995. ¹ Risk increases with age, beginning at age 50, and is also higher among African American men. Because it is more common in older men, prostate cancer ranks 21st among cancers in years of potential life lost. ² The age-adjusted death rate from prostate cancer increased by over 20% between 1973 and 1991. ³ The lifetime risk of dying from prostate cancer is 3.4% for American men. ³ The reported incidence of prostate cancer has increased in recent years by 6% per year, a trend attributed to increased early detection efforts. ⁴ Because local extension beyond the capsule of the prostate rarely produces symptoms, about one to two thirds of patients already have local extracapsular extension or distant metastases at the time of diagnosis. ⁵ Ten-year survival rates are 75% when the cancer is confined to the prostate, 55% for those with regional extension, and 15% for those with distant metastases. ⁶ The potential morbidity associated with progression of prostate cancer is also substantial, including urinary tract obstruction, bone pain, and other sequelae of metastatic disease.

The principal screening tests for prostate cancer are the digital rectal examination (DRE), serum tumor markers (e.g., prostate-specific antigen [PSA]), and transrectal ultrasound (TRUS). The reference standard for these tests is pathologic confirmation of malignant disease in tissue obtained by biopsy or surgical resection. The sensitivity and specificity of screening tests for prostate cancer cannot be determined with certainty, however, because biopsies are generally not performed on patients with negative screening test results. False-negative results are unrecognized unless biopsies are performed for other reasons (e.g., abnormal results on another screening test, tissue obtained from transurethral prostatic resection). The resulting incomplete information about the number of true- and false-negative results makes it impossible to properly calculate sensitivity and specificity. Only the positive predictive value (PPV) -- the probability of cancer when the test is positive -- can be calculated with any confidence.

Even the PPV is subject to uncertainty because of the inaccuracies of the usual reference standard. Needle biopsy, the typical reference standard used for calculating sensitivity and specificity, has limited sensitivity. One study suggested that as many as 19% of patients with an initially negative needle biopsy (but abnormal screening test results) had evidence of cancer on a second biopsy. ⁷ Moreover, studies vary in the extent to which the gland is sampled during needle biopsy. Recent studies, in which larger numbers of samples are obtained from multiple sections of the gland, provide a different reference standard than the more limited needle biopsies performed in older studies. These methodologic problems account for the large variation in the reported sensitivity, specificity, and PPV of prostate cancer screening tests and the current controversy over their true values.

DRE is the oldest screening test for prostate cancer. Its sensitivity is limited, however, because the examining finger can palpate only the posterior and lateral aspects of the gland. Studies suggest that 25-35% of tumors occur in portions of the prostate not accessible to the examining finger. ⁸ In addition, Stage A tumors, by definition, are nonpalpable. Most recent studies report that DRE has a sensitivity of 55-68% in detecting prostate cancer in asymptomatic men, ^9,10 but values as low as 18-22% have also been reported in studies using different screening protocols. ^11,12 The DRE also has limited specificity, producing a large proportion of false-positive results. The reported PPV in asymptomatic men is 6-33% ^10,13-15 but appears to be somewhat higher when performed by urologists rather than by general practitioners. ¹⁶

Elevations in certain serum tumor markers (e.g., PSA and prostatic acid phosphatase) provide another means of screening for prostate cancer. In screening studies, a PSA value greater than 4 ng/dL has a reported sensitivity of over 80% in detecting prostate cancer in asymptomatic men, ¹⁰ although a sensitivity as low as 29% has also been reported in studies using different screening protocols. ¹¹ Prostatic acid phosphatase has a much lower sensitivity (12-20% for Stage A and B disease) and PPV (below 5%) than PSA, ¹⁷ and its role in screening has largely been replaced by PSA. PSA elevations are not specific for prostate cancer. Benign prostatic conditions such as hypertrophy and prostatitis can produce false-positive results about 25% of men with benign prostatic hypertrophy (BPH) and no malignancy have an elevated PSA level. ¹⁸

In most screening studies involving asymptomatic men, the reported PPV of PSA in detecting prostate cancer is 28-35%. ^10,19-21 In many instances, however, other screening tests (e.g., DRE) are also positive. The PPV of PSA when DRE is negative appears to be about 20%. ²² It is unclear whether the same PPV applies when screening is performed in the general population. Participants in most screening studies are either patients seen in urology clinics or volunteers recruited from the community through advertising. Studies suggest that such volunteers have different characteristics than the general population. ²³ For example, in one screening study, 53% of the volunteers had one or more symptoms of prostatism. ¹⁰ Since PPV is a function of the prevalence of disease, routine PSA testing of the general population, if it had a lower prevalence of prostate cancer than volunteers, would generate a higher proportion of false-positive results than has been reported in the literature. A significant difference in prevalence in the two populations has not, however, been demonstrated.

Several techniques have been proposed to enhance the specificity and PPV of the PSA test. The serum concentration of PSA appears to be influenced by tumor volume, and some investigators have suggested that PSA density (the PSA concentration divided by the gland volume as measured by TRUS) may help differentiate benign from malignant disease. ^24-26 According to these studies, a PSA density greater than 0.15 ng/mL may be more predictive of cancer. Other studies suggest that the rate of change (PSA velocity), rather than the actual PSA level, is a better predictor of the presence of prostate cancer. An increase of 0.75 ng/mL or higher per year has a reported specificity of 90% and 100% in distinguishing prostate cancer from BPH and normal glands, respectively. ²⁷ PSA values tend to increase with age, and investigators have therefore proposed age-adjusted PSA reference ranges. ^28,29 Current evidence is inadequate to determine the relative superiority of any of these measures or to prove conclusively that any is superior to absolute values of PSA. ³⁰ The most effective method to increase the PPV of PSA screening is to combine it with other screening tests. In a large screening study, the combination of an elevated PSA and abnormal DRE achieved a PPV of 49%. Even with this improved accuracy, however, combined DRE and PSA screening led to the performance of needle biopsies on 18% of the screened population, ¹⁰ raising important public policy issues (see below).

A large proportion of cancers detected by PSA screening may be latent cancers, indolent tumors that are unlikely to produce clinical symptoms or affect survival. Autopsy studies indicate that histologic evidence of prostate cancer is present in about 30% of men over age 50. The reported prevalence of prostate cancer in men without previously known prostate cancer during their lifetimes is 10-42% at age 50-59, 17-38% at age 60-69, 25-66% at age 70-79, and 18-100% at age 80 and older. ^31-37 Recent autopsy studies have even found evidence of carcinoma in 30% of men aged 30-49. ³⁸ Although patients who undergo autopsy may not be entirely representative of the general population, these prevalence rates, combined with census data, ³⁹ suggest that millions of American men have prostate cancer. Fewer than 40,000 men in the U.S. die each year from prostate cancer, however, suggesting that only a subset of cancers in the population are clinically significant. Natural history studies indicate that most prostate cancers grow slowly over a period of many years. ⁴⁰ Thus, many men with early prostate cancer (especially older men) will die of other causes (e.g., coronary artery disease) before their cancer becomes clinically apparent. Because a means of distinguishing definitively between indolent and progressive cancers is not yet available, widespread screening is likely to detect a large proportion of cancers whose effect on future morbidity and mortality is uncertain.

Recent screening studies have suggested, however, that cancers detected by PSA screening may be of greater clinical importance than latent cancers found on autopsy. Studies of asymptomatic patients with nonpalpable cancers detected through PSA screening have reported extracapsular extension, poorly differentiated cell types, tumor volumes exceeding 3 mL, and metastases in 31-38% of cancers that were pathologically staged. ^20,41-43 In a retrospective review of radical prostatectomies performed on patients with nonpalpable prostate cancer detected by PSA screening, 65% had a volume greater than 1 mL, and surgical margins were positive in 26% of cases. ⁴⁴ In a similar series, the mean tumor volume was 7.4 mL and 30% of the tumors had penetrated the capsule. ⁴⁵

The sensitivity of PSA for clinically important cancers was examined in a recent nested case-control study among 22,000 healthy physicians participating in a long-term clinical trial. ⁴⁶ Archived blood samples collected at enrollment were compared for 366 men who were diagnosed clinically with prostate cancer during a 10-year follow-up period and 1,098 matched controls without cancer. PSA was elevated (>4 ng/mL) in 46% of the men who subsequently developed prostate cancer and 9% of the control group (i.e., sensitivity 46%, specificity of 91%). For cancers diagnosed within the first 4 years of follow-up, the sensitivity of PSA was 87% for aggressive cancers but only 53% for nonaggressive cancers (i.e., small, well-differentiated tumors), suggesting that PSA is more sensitive for clinically important disease. Given the low incidence of aggressive prostate cancer in this study (1% over 10 years), the reported specificity of 91% would generate a PPV (10-15%) that is lower than that reported from studies using routine biopsies (28-35%). ¹⁰ Furthermore, this study could not address the central question of whether PSA would have identified aggressive cancers at a potentially curable stage.

TRUS is a third means of screening for prostate cancer, but its performance characteristics limit its usefulness as a screening test. In most studies, TRUS has a reported sensitivity of 57-68% in detecting prostate cancer in asymptomatic men. ^9,10 Because TRUS cannot distinguish between benign and malignant nodules, its PPV is lower than PSA. Although a PPV as high as 31% has been reported for TRUS, ⁴⁷ its reported PPV when other screening tests are normal is only 5-9%. ^15,19 Even when cancers are detected, the size of tumors is often underestimated by TRUS. The discomfort and cost of the procedure further limit its role in screening.

There is currently no evidence that screening for prostate cancer results in reduced morbidity or mortality, in part because few studies have prospectively examined the health outcomes of screening. A case-control study found little evidence that DRE screening prevents metastatic disease the relative risk of metastatic prostate cancer for men with one or more screening DREs compared with men with none was 0.9 (95% confidence interval, 0.5-1.7). ⁴⁸ A cohort study also reported little benefit from DRE screening, ⁴⁹ but its methodologic design has been criticized. Randomized controlled trials of DRE and PSA screening, which are expected to provide more meaningful evidence than is currently available, are currently under way in the U.S. and Europe. ⁵⁰ The results of these studies, however, will not be available for over a decade. Therefore, recommendations for the next 10 years will depend on indirect evidence for or against effectiveness.

Indirect evidence that early detection of prostate cancer improves outcome is limited. Survival appears to be longer for persons with early-stage disease 5-year survival is 87% for Stage A (nonpalpable) tumors, 81% for Stage B (palpable, organ-confined cancer), 64% for Stage C (local extracapsular penetration), and 30% for Stage D (metastatic). ⁵ Due to recent screening efforts, prostate cancer is now increasingly diagnosed at a less advanced stage. As with survival advantages observed with other cancers, however, it is not known to what extent lead-time and length biases account for differences in observed survival rates (see Chapter ii). The frequently indolent nature of prostate cancer makes length bias a particular problem in interpreting stage-specific survival data. Successful treatment of indolent tumors may give a false impression that "cure" was due to treatment. Prostate cancers detected through screening are more likely to be organ-confined than cancers detected by other means. ²⁰ Proponents of radical prostatectomy often argue that such cancers are potentially curable by removing the gland. As already noted, however, current evidence is inadequate to determine with certainty whether these organ-confined tumors are destined to progress or affect longevity thus the need for treatment is often unclear.

Even if the need for treatment is accepted, the effectiveness of available treatments is unproven. Stage C and Stage D disease are often incurable, and the efficacy of treatment for Stage B prostate cancer is uncertain. Currently available evidence about the effectiveness of radical prostatectomy, radiation therapy, and hormonal treatment derives largely from case-series reports without internal controls, usually involving carefully selected patients and surrogate outcome measures for monitoring progression (e.g., PSA levels). ^51-55 Although men treated for organ-confined prostate cancer have a normal life expectancy, it is not clear how much their prognosis owes to treatment. The only randomized controlled trial of prostate cancer treatment, which compared radical prostatectomy with expectant management, reported no difference in cumulative survival rates over 15 years, but the study was conducted in the 1970s and suffered from several design flaws. ^56,57 Randomized controlled trials to evaluate the effectiveness of current therapies for early disease are being launched in the U.S. and Europe, but results are not expected for 10-15 years. ^58,59

Some observational studies suggest that survival for early-stage prostate cancer may be good even without treatment. A Swedish population-based cohort study of men with early-stage, initially untreated prostate cancer found that, after 12.5 years, 10% had died of prostate cancer and 56% had died of other causes. The 10-year disease-specific survival rate (adjusted for deaths from other causes) for the study population was 85%. Cancer-related morbidity was significant, however. Over one third of the cancers progressed through regional extension, and 17% metastasized. The patient's age and the tumor stage did not significantly influence survival rates, but tumor grade (degree of differentiation) did affect survival the 5-year survival rate was only 29% for poorly differentiated tumors. ^59-61 Critics of the study have argued that the high survival rates were due to the relatively large proportion of older men and of tumors detected incidentally during transurethral prostatic resection, and that Swedish data are not generalizable to the U.S. ^22,62 Other studies have reported similar results in one series of selected men with well- and moderately differentiated cancer and extracapsular (nonmetastatic) extension, 5- and 9-year survival rates were 88% and 70%, respectively, without treatment. ⁶³ Reported 10-year disease-specific survival for expectant management of palpable but clinically localized prostate cancer is 84-96%. ^64-66 Finally, it is unclear whether reported survival rates in these studies, in which many cancers were detected without screening, are generalizable to screen-detected cancers.

Reviewers have attempted to compare the efficacy of treatment and watchful waiting by pooling the results of uncontrolled studies. An analysis of six studies concluded that conservative management of clinically localized prostate cancer (delayed hormone therapy but no surgical or radiation therapy) was associated with a 10-year disease-specific survival rate of 87% for men with well- or moderately differentiated tumors and 34% for poorly differentiated tumors. ⁶⁷ The assumptions used in the model are not universally accepted, however. ^68,69 A structured literature review concluded that the median annual rates of metastatic disease and prostate cancer mortality were 1.7% and 0.9%, respectively, without treatment. ⁷⁰ This study was criticized for including a large proportion of patients with well-differentiated tumors and those receiving early androgen deprivation therapy. ⁷¹ Another review concluded that the annual rates for metastasis and mortality were higher (2.5% and 1.7%, respectively), but the review was limited to patients with palpable clinically localized cancers and excluded studies of cancers found incidentally at prostatectomy. In this population, disease-specific survival was estimated to be 83% for deferred treatment, 93% for radical prostatectomy, and 74% for external radiation therapy. ⁷² Thus, the effectiveness of treatment when compared with watchful waiting remains uncertain.

Uncertainties about the effectiveness of treatment are important because of its potentially serious complications. Needle biopsy, the diagnostic procedure performed on about 20% of men screened with DRE and PSA, ¹⁰ is generally safe but results in infection in 0.3-5% of patients, septicemia in 0.6% of patients, and significant bleeding in 0.1% of patients. ^19,73-75 The potential adverse effects of radical prostatectomy are more substantial. Although urologists at specialized centers report operative mortality rates of 0.2-0.3%, ^55,76 published rates in clinical studies and national databases range between 0.7% and 2%. ^6,70,77-79 An examination of Medicare claims files estimated that the 30-day mortality rate was 0.5%. ⁸⁰ The reported incidence of impotence varies between 20% and 85%, ^{11,51,70,79,81,82} depending on definitions for impotence and whether bilateral nerve-sparing techniques are used. Other complications of prostatectomy include incontinence (2-27%), urethral stricture (10-18%), thromboembolism (10%), and permanent rectal injuries (3%). ^{11,51,70,77,83-87} A study of Medicare patients who underwent radical prostatectomy in the late 1980s reported a 30-day operative mortality rate of 1% and a 4-5% incidence of perioperative cardiopulmonary complications. Over 30% wore pads to control wetting, 6% underwent corrective surgery for incontinence, and 2% required the use of an indwelling catheter. Over 60% reported partial erections and 15% underwent treatment for sexual dysfunction 20% had dilatations or surgical procedure for strictures. ⁸⁸ Studies of generally healthy and younger patients who have undergone radical prostatectomy in recent years have noted considerably fewer complications. ⁵⁵

Complications of radiation therapy include death (about 0.2-0.5%), acute gastrointestinal and genitourinary complications (8-43%), chronic complications requiring surgery or prolonged hospitalization (2%), impotence (40-67%), urethral stricture (3-8%), and incontinence (1-2%). ⁸⁹ Three-dimensional conformal radiotherapy, a recently introduced technique for more precise, high-dose treatment, is reported to produce acute and chronic gastrointestinal or genitourinary complications in 55-76% and 11-12% of patients, respectively. ⁹⁰ Complication rates in studies of radiation therapy cannot be compared with confidence to reported complication rates for surgery because of differences in study designs and patient populations.

Recent decision analyses have combined current estimates of the benefits and harms to predict whether early treatment improves survival. A frequently cited decision analysis for men aged 60-75 concluded that, in most cases of clinically localized prostate cancer, neither surgery nor radiation therapy significantly improved life expectancy. ⁹¹ According to the model, treatment generally results in less than 1 year of improvement in quality-adjusted survival. In men over age 70, the analysis suggested that treatment was more harmful than watchful waiting. The study has been criticized because the subjects consisted largely of older men with low-volume, low-grade tumors and because the probability estimates used in the model may be incorrect. ^71,92 Defenders of the study note that the data were adjusted for age and tumor grade (but not stage). Retrospective quality-of-life analyses have reported similar findings, noting that men who have undergone radical prostatectomy or radiation therapy for localized prostate cancer generally report lower quality of life due to impaired sexual, urinary, and bowel function than untreated men, even after controlling for the sexual and urinary dysfunction that is common in this age group. ⁹³

Other decision analyses have examined whether screening itself improves survival. Although older analyses suggested a modest benefit from screening, ^94,95 more recent models have reached more pessimistic conclusions when quality-of-life adjustments are incorporated. One analysis concluded that screening and treatment result in an average loss of 3.5 quality-adjusted months of life. ⁹⁶ Another decision analysis concluded that one-time screening of men aged 50-70 with either DRE or PSA would increase life expectancy by 0-0.2 days and 0.6-1.6 days, respectively, but quality-adjusted life would be decreased by 1.8-7.1 days and 2.1-9.5 days, respectively, per patient screened. ⁹⁷ The assumptions and calculations used in this model have also been criticized. ⁹⁸ A recent analysis of annual screening after age 50 concluded that screening would result in an average loss of 0.7 quality-adjusted life-years per patient screened. ^98a

The American Cancer Society ⁹⁹ recommends an annual DRE for both prostate and colorectal cancer, beginning at age 40. It recommends that the annual examination of men age 50 and older should include a serum PSA measurement and that PSA screening should begin at age 40 for African American men and those with a family history of prostate cancer. ¹⁰⁰ Similar recommendations have been issued by the American Urological Association ¹⁰¹ and the American College of Radiology. ¹⁰² In 1994, the Food and Drug Administration expanded the licensure for the PSA test to include screening. ¹⁰³ The Canadian Task Force on the Periodic Health Examination (CTF) recommended against the routine use of PSA or TRUS as part of the periodic health examination while recognizing the limitations of DRE, they concluded that the evidence was not sufficient to recommend that physicians discontinue use of DRE in men aged 50-70. ¹⁰⁴ A 1995 report by the Office of Technology Assessment concluded that research to date had not determined whether or not systematic early screening for prostate cancer with PSA or DRE would save lives, and that the choice to have screening or forego it would depend on patient values. ¹⁰⁵ The recommendations of the American College of Physicians and American Academy of Family Physicians are currently under review. In 1992, the American Urological Association concluded that the value of TRUS as an independent screening procedure has not been established and should be reserved for patients with an abnormal DRE or PSA. ¹⁰⁶

In summary, prostate cancer is a serious public health problem in the United States, accounting for 35,000-40,000 deaths each year and substantial morbidity from disease progression and metastatic complications. Autopsy studies indicate, however, that these cases arise from a much larger population of latent prostate cancers that are present in over nine million American men. Although screening tests such as PSA have adequate sensitivity to detect clinically important cancers at an early stage, they are also likely to detect a large number of cancers of uncertain clinical significance. The natural history of prostate cancer is currently too poorly understood to determine with certainty which cancers are destined to produce clinical symptoms or affect survival, which cancers will grow aggressively, and which will remain latent. Prostate cancer has a complex biology with many unanswered questions about heterogeneity, tumor-host interactions, and prognostic stratification.

More fundamentally, there is no evidence to determine whether or not early detection and treatment improve survival. For men with well- and moderately differentiated disease, treatment appears to offer little benefit over expectant management, whereas the most aggressive tumors may have spread beyond the prostate by the time they are detected by screening. Observed survival advantages for men with early-stage disease may be due to length bias and other statistical artifacts rather than an actual improvement in clinical outcome. Although it is possible that treatment is beneficial for an unknown proportion of men with early prostate cancer, definitive evidence regarding effectiveness will not be available for over a decade, when ongoing randomized controlled trials are completed. In the interim years, during which thousands of deaths from prostate cancer are predicted, screening might be justified for its potential benefit were it not for its potential harms. Widespread screening will subject many men to anxiety from abnormal test results and the discomfort of prostate biopsies aggressive treatment for screen-detected cancers will expose thousands of men to the risks of incontinence, impotence, death, and other sequelae without clear evidence of benefit. Decision-analysis models suggest that the negative impact of these complications on quality of life may outweigh the potential benefits of treatment, but the designs and assumptions of these models are controversial. The absence of proof that screening can reduce mortality from prostate cancer, together with the clear potential that screening will increase treatment-related morbidity, argues against a policy of routine screening in asymptomatic men.

The economic implications of widespread prostate screening, although not a principal argument against its appropriateness, also warrant attention. A full discussion of the cost effectiveness of prostate screening is beyond the scope of this chapter. Moreover, cost effectiveness cannot be properly determined without evidence of clinical effectiveness. Nonetheless, it is clear that routine screening of the 28 million American men over age 50, ³⁹ as recommended by some groups, would be costly. Researchers have predicted that the first year of mass screening would cost the country $12-28 billion. ^6,11 This investment might be worthwhile if the morbidity and mortality of prostate cancer could be reduced through early detection -- given certain assumptions, prostate cancer screening might even achieve cost-benefit ratios comparable to breast cancer screening ¹⁰⁷ -- but there is currently little evidence to support these assumptions. The costs of this form of screening, with its emphasis on older men, is likely to increase in the future with the advancing age of the United States population the number of American men over age 55 is expected to nearly double in the next 30 years, from 23 million men in 1994 to 44 million by 2020. ³⁹

There is some evidence that the recent increase in prostate screening may be generating a poorly controlled expansion in the performance of radical prostatectomies, creating an unnecessary iatrogenic morbidity in a growing population of surgical patients. The rising incidence of prostate cancer due to increased screening has been accompanied by a tripling in rates for radical prostatectomy in the U.S. ⁴ If early detection and treatment are effective, they are most likely to benefit men under age 70 rather than older men. As already noted, 10-year survival for early-stage prostate cancer approaches 90%. Thus, most men over age 70, who face a life expectancy of just over 10 years, are more likely to die of other causes than of prostate cancer. Subjecting these men to the risks of biopsy and treatment is often unwarranted, and many proponents of prostate screening therefore recommend against screening after age 70. Nonetheless, studies indicate that radical prostatectomy rates for men aged 70-79 increased 4-fold in 1984-1990, and the trend appears to be continuing in this decade. Population-based rates for prostatectomy in men aged 70-79, many of whom are unlikely to benefit from the procedure, appear to be the same as in men aged 60-69. ⁷⁸ According to an American College of Surgeons survey, one out of three men undergoing radical prostatectomy in 1990 was age 70 or older. ⁷⁹

The lack of evidence regarding the benefits of prostate screening and the considerable risks of adverse effects make it important for clinicians to inform patients who express an interest in screening about the consequences of testing before they consent to screening. Although such counseling is proper for all forms of screening, the need for informed consent is especially important for prostate cancer screening because of current uncertainty about its effectiveness and because the proper choice for an individual is highly dependent on personal preferences. Screening is more likely to be chosen by men with strong fears of prostate cancer and by those who can accept the risks of incontinence, impotence, and other treatment complications. Screening is less likely to be chosen by men who are skeptical of the risks of cancer and the effectiveness of treatment and who have strong fears that treatment complications will jeopardize their quality of life.

CLINICAL INTERVENTION

Routine screening for prostate cancer with DRE, serum tumor markers (e.g., PSA), or TRUS is not recommended ("D" recommendation). Patients who request screening should be given objective information about the potential benefits and harms of early detection and treatment. Patient education materials that review this information are available. ¹⁰⁸ If screening is to be performed, the best-evaluated approach is to screen with DRE and PSA and to limit screening to men with a life expectancy greater than 10 years. There is currently insufficient evidence to determine the need and optimal interval for repeat screening or whether PSA thresholds must be adjusted for density, velocity, or age.

The draft update of this chapter was prepared for the U.S. Preventive Services Task Force by Steven H. Woolf, MD, MPH. See also the relevant background paper: U.S. Preventive Services Task Force. Screening for prostate cancer: commentary on the recommendations of the Canadian Task Force on the Periodic Health Examination. Am J Prev Med 199410:187-193.

Cancer of the lung is the leading cause of death from cancer in both men and women in the U.S. An estimated 172,000 new cases will be diagnosed in 1995, with an estimated 153,000 deaths. ¹ Lung cancer has one of the poorest prognoses of all cancers, with a 5-year survival rate of less than 13%. ¹ Important risk factors for lung cancer include tobacco use and certain environmental carcinogen exposures. Tobacco is associated with 87% of all cases of cancer of the lung, trachea, and bronchus. ²

The chest radiograph (x-ray) and sputum cytomorphologic examination (cytology) lack sufficient accuracy to be used in routine screening of asymptomatic persons. The accuracy of the chest x-ray is limited by the capabilities of the technology and observer variation among radiologists. Suboptimal technique, insufficient exposure, and poor positioning and cooperation of the patient can obscure pulmonary nodules or introduce artifacts. ³ Radiologists frequently disagree on the interpretation of chest x-rays (interobserver variability). In one study, over 40% of these disagreements were considered potentially significant. ⁴ Most errors are false-negative interpretations, and pulmonary and hilar masses are among the most commonly missed diagnoses. From 10% to 20% of the incorrect radiologic diagnoses or indeterminate results require follow-up testing for clarification. ⁴ Interpretation of chest x-rays by primary care physicians is less accurate than interpretation by radiologists. Discrepancies were identified in 58% of chest x-rays read by both family physicians and radiologists. ⁵ Current radiographic technologies require greater than 20 doublings of tumor size to reach the 1 cm³ needed for the lower limit of chest imaging sensitivity. By the time lung cancer is suspected on chest x-ray, micrometastatic dissemination has often occurred, limiting the effectiveness of early detection. ⁶

Furthermore, the yield of screening chest radiography is low, largely due to the low prevalence of lung cancer in asymptomatic individuals, even those at high risk. Of the initial 31,360 screening x-rays of asymptomatic smokers in the National Cancer Institute (NCI) Cooperative Early Lung Cancer Detection Program, 256 (0.82%) were interpreted as "suspicious for cancer," and only 121 (0.39% of those screened) were diagnosed with lung cancer. ⁷ Other studies have confirmed a low yield of performing chest x-rays on asymptomatic persons. ^8,9

Sputum cytology is an even less effective screening test, largely due to its low sensitivity compared to chest x-ray. ⁶ Of the 160 lung cancers detected by dual screening in the NCI study, 123 (77%) would have been detected by chest x-ray alone and 67 (42%) would have been detected by cytologic examination alone. ⁷ The majority of incident cases detected in subsequent screenings were detected by chest x-ray. ¹⁰ In other trials using dual screening, sensitivity of chest x-ray ranges from 40% to 50%, versus 10% to 20% for sputum cytology. ¹¹ Mass screening to detect lung cancer with tests that lack a high sensitivity will be inefficient. ¹²

Lung cancer is usually asymptomatic until it has reached an advanced stage, when the treatment outcome is poor. Five-year survival for all stages is 11-14% for Stage I it is 42-47%. ¹ Under optimal conditions, survival can be higher. ^10,12,13 Early detection of Stage I cases through screening might be expected to improve survival, but the small amount of available evidence does not show that screening reduces lung cancer mortality.

The efficacy of chest radiographic screening for lung cancer was first investigated in the 1960s. A controlled prospective study involving over 55,000 persons found that those receiving chest x-rays every 6 months had a larger proportion of resectable tumors, but mortality for lung cancer remained the same when compared with controls who received examinations only at the beginning and end of the trial. ¹⁴ Similar findings were reported in the Philadelphia Pulmonary Neoplasm Research Project ¹⁵ and, more recently, in a case-control study. ¹⁶ In addition, the results of one of the three centers participating in the NCI Cooperative Early Lung Cancer Detection Program provide indirect evidence of the limited efficacy of radiographic screening. In this study, persons receiving chest x-rays and sputum cytology every 4 months had the same lung cancer mortality as persons advised to obtain annual testing. ¹⁷

No prospective randomized study with adequate follow-up time has compared radiographic screening with no screening. A case-control study in Japan compared the screening histories of 273 fatal cases of lung cancer to 1,269 controls, and although the data suggest a trend toward a decreased risk of lung cancer mortality in those screened with chest x-rays (with or without sputum cytologic tests), the difference was not statistically significant. ¹⁸

Three large clinical trials published by the NCI Cooperative Early Lung Cancer Detection Program examined the efficacy of dual screening (chest x-ray and sputum cytology) in over 30,000 male smokers aged 45 or older. ^7,10,19-23 Two trials comparing annual dual screening with annual radiographic screening tested the incremental benefit of adding sputum cytology to radiographic screening. ^20,21 The third trial, which compared dual screening every 4 months with advice to receive the same tests annually, examined the benefit of frequent dual screening compared to usual medical care. ²² In each study, lung cancer mortality did not differ between experimental and control groups. Although early-stage, resectable tumors were more common and 5-year survival significantly higher in groups receiving regular dual screening, lead-time and length biases may have been responsible for these findings. A randomized prospective trial of dual screening in Czechoslovakia produced similar results. ²⁴ The investigators found no substantial difference in the number or causes of death between study groups.

The NCI is currently conducting the multicenter PLCO (prostate, lung, colorectal, and ovarian cancers) Trial, which will compare annual chest radiographic testing with usual care in both men and women. ²⁵

No organizations currently recommend routine screening of either the general population or of smokers for lung cancer with either chest x-rays or sputum cytology. ^26-31

Lung cancer is the leading cause of cancer mortality. Although screening may increase early detection of resectable early cancers, controlled trials provide no significant evidence that lung cancer screening reduces mortality from this disease. To the weakness of the evidence for screening must be added the substantial costs of routine testing, ⁹ including false-positive results that lead to unnecessary expense and morbidity from follow-up procedures. ³² Current research and clinical trials of chemoprevention, ³³ as well as research in early detection markers such as monoclonal antibodies, ^6,34 may improve efficacy in prevention or early identification of lung cancer. Primary prevention -- mainly through discouraging tobacco use -- is a more effective strategy than screening to reduce lung cancer morbidity and mortality. ¹¹ Unless ongoing trials find a benefit of periodic chest x-rays, the cost, inconvenience, and potential harms of screening cannot be justified.

CLINICAL INTERVENTION

Routine screening of asymptomatic persons for lung cancer with chest radiography or sputum cytology is not recommended ("D" recommendation). All patients should be counseled against tobacco use (see Chapter 54).

The draft update of this chapter was prepared for the U.S. Preventive Services Task Force by Kathlyne Anderson, MD, MOH, and Donald M. Berwick, MD, MPP.

12. Screening for Skin Cancer Including Counseling to Prevent Skin Cancer

Over 800,000 new cases of skin cancer are diagnosed each year. ¹ More than 95% of these are basal cell (BCC) and squamous cell (SCC) carcinomas, also referred to as nonmelanomatous skin cancers (NMSC). These are highly treatable and rarely metastasize, but local tissue destruction may cause disfigurement or functional impairment if these tumors are not detected early. ² They account for approximately 2,100 deaths each year. ¹ The risk of NMSC is increased by a personal history of NMSC older age light eyes, skin, or hair poor ability to tan and substantial cumulative lifetime sun exposure. ^3-5

Malignant melanoma (MM) is less common than NMSC but is far deadlier. An estimated 34,100 new cases and 7,200 deaths (2.2/100,000 population) from MM occurred in the U.S. in 1995. ^1,6 The incidence rate varies by race: 9.2/100,000 in whites, 1.9/100,000 in Hispanics, and 0.7-1.2/100,000 in blacks and Asians. ⁷ In the past two decades, increases of 4%/year in MM incidence and nearly 2%/year in mortality have been reported. ^6,8 With a median age at diagnosis of 53 years, ⁹ MM ranks second among adult-onset cancers in years of potential life lost per death. ¹⁰ Significant risk factors for MM besides white race include melanocytic precursor or marker lesions (e.g., atypical moles, certain congenital moles), increased numbers of common moles, immunosuppression, and a family or personal history of skin cancer, especially MM. ^11-23 Fewer than 5% of the population have melanocytic precursor lesions, which have a high malignant potential and may account for as many as 40% of melanomas. ²⁴ For persons with the rare familial atypical mole and melanoma (FAM-M) syndrome, the MM risk is increased 100-fold or more, ^11-13 and the cumulative lifetime risk may approach 100%. ¹¹ Persons with intermittent intense sun exposure or severe sunburns in childhood also appear to have an increased risk that varies by MM subtype. ^{17,19,20,25-27} Persons with poor tanning ability, freckles, or light skin, hair, and eye color may have a small increased risk of MM. ^17-20,28

The principal screening test for skin cancer is physical examination of the skin by a clinician. Detection of a suspicious lesion constitutes a positive screening test, which then should be confirmed by skin biopsy. The true sensitivity and specificity of the skin examination are unknown. ²⁹ In virtually all studies evaluating the accuracy of the skin examination, only clinically suspicious lesions were biopsied and only screen-positive persons were followed therefore, sensitivity and specificity cannot be determined accurately. One study of persons presenting to free skin cancer screening clinics for screening by dermatologists estimated sensitivity of the examination using population incidence rates to estimate false-negative rates sensitivities were 97% for MM, 94% for BCC, and 89% for SCC. ³⁰ Two or more risk factors for skin cancer were present in 78% of those screened, however, so sensitivities may have been overestimated. ³¹ Among persons with positive screening clinic examinations, the likelihood of histologic confirmation has been reported to be 40% for MM, 43% and 57% for BCC, and 14% and 75% for SCC. ^30,32 For persons presenting for skin examination to skin clinics, the likelihood of histologic confirmation given a clinical diagnosis of MM is 38-64% for dermatologists and 72-84% for skin cancer specialists. ^33-35 Among patients biopsied by dermatologists who had histologically confirmed MM, the diagnosis was suspected in 62-85% of cases. ^34,36 In a randomized community study evaluating screening by expert dermatologists, histologic examination confirmed the clinical diagnosis of SCC in 38% of cases and of BCC in 59%. ³⁷ In vivo epiluminescence microscopy appears to improve dermatologists' diagnostic accuracy for skin lesions, ^38,39 but it is not a practical screening tool for primary care physicians.

Primary care physicians and others lacking specialized training in dermatology would be expected to have greater difficulty in evaluating skin lesions. Several studies have reported that, compared to dermatologists, nondermatologists make significantly fewer correct diagnoses of skin lesions (including MM and BCC) from color photographs. ^40-42 In one such study, at least five of six photographs of MM were correctly identified by 69% of the dermatologists but by only 12% of the nondermatologists at least one of two atypical moles was recognized by 96% of the dermatologists but by only 42% of the nondermatologists. ⁴⁰

One factor affecting the yield of screening for skin cancer is the proportion of the body surface examined. Only 20% of MM occur on normally exposed body surfaces, in contrast to 85-90% of NMSC. ^9,27 Dermatologists estimate that detection of MM is 2-6 times more likely with a total-body skin examination (TSE). ^43,44 A second factor that affects yield is the frequency of examination. If the interval between examinations is too long, new cancers may not be detected before they have progressed to an advanced stage. There are no published data available, however, with which to determine the optimal frequency of examination in the general population annual or biennial intervals have been recommended on the basis of clinical judgment. Poor patient compliance with recommendations for yearly total skin examinations may reduce the effectiveness of this intervention in one study, only 22/524 (4.2%) patients returned for the yearly TSE that was recommended on the first visit. ⁴⁵

In terms of risk to the patient, no serious adverse effects associated with TSE and follow-up biopsy have been reported, and experts view it as acceptable and safe. ³³ Embarrassment may be an adverse effect, ⁴⁶ because modesty is one of the main reasons given for refusing a TSE. ⁴⁴ Medical expenses may also be increased because office visits must be lengthened to accommodate complete undressing, "chaperoning," examination, and redressing, ⁴⁶ and because more frequent referrals and biopsies are likely to result. There are no controlled studies evaluating any adverse effects of TSE.

Patient self-examination would be expected to be less accurate than physician examination in evaluating skin lesions. One study evaluated patients' ability to apply a seven-point checklist to the skin lesion that prompted their referral to a dermatologist. ³⁵ The patient checklist had a sensitivity of 71%, specificity of 99%, and positive predictive value of 7% for MM diagnosis, using the dermatologist's clinical diagnosis as the "gold standard." The sensitivity and specificity using histologic diagnosis as the reference standard would likely be lower. No data were found evaluating the ability of patients to detect suspicious lesions, the accuracy of periodic skin self-examination, or the efficacy of self-examination instructions in reducing errors.

Early treatment might reduce morbidity and disfigurement for patients with BCC and SCC, ² but no studies were found that have evaluated whether such cancers discovered by screening have a better outcome than those which present clinically.

For MM, there have also been no controlled trials evaluating the impact of screening on morbidity or mortality. A time-series study of an educational campaign to encourage MM screening by primary providers in Scotland found a trend toward a reduction in both thick tumors (p < 0.05) and mortality (not statistically tested) in women (but not men) after the campaign. ⁴⁷ Women were overrepresented in the screened population, which may explain the difference in mortality by sex. No control group was included, so differences due to historical trends or other factors cannot be excluded. The authors noted that in Denmark, which has comparable incidence rates, the MM mortality in women rose during this period.

More data are available on the effect of screening by dermatologists on MM thickness. In two large case series of persons with atypical moles who were screened regularly by dermatologists, all MM detected were either thin (< 0.89 mm) or in situ. ^13,15 Time series in the general population, and cohort studies in FAM-M syndrome kindreds and in persons with a prior MM, have reported that screening by dermatologists detected significantly thinner tumors when compared to historical population, kindred, or personal index cases. ^47-51 Several countries have reported a consistent decline over the past 3-4 decades in median thickness of MM, although this decline has not been directly linked to screening programs. ^52,53 None of these studies used concurrent unscreened controls to differentiate the effects of screening programs from historical trends or lead-time and length biases.

If clinician screening does in fact result in detection of significantly thinner MM, mortality might be reduced. Case series and a prediction model (validated on subsequent incident cases) have reported that survival is directly related to lesion thickness at the time of resection. ^9,39,54-56 For example, 5-year survival is 95-99% for persons with lesions <= 0.75 mm, 66-77% for 1.51-4.0 mm, 41-51% for 4.76-9.75 mm, and 5% for those with disseminated MM. The likelihood of recurrence after resection also correlates with lesion thickness. A MM < 1 mm thick is associated with an 8-year disease-free survival rate of 90%, compared with 74% for lesions 1-2 mm thick. ⁵⁷ Although it is possible that lead-time and length biases account for some of these differences, these data suggest that persons in whom thinner MM are detected experience a better outcome than those detected with more advanced disease.

Data on the effectiveness of early detection by skin self-examination are limited. Preliminary analyses from a population-based case-control study retrospectively evaluating the efficacy of skin self-examination in patients with MM suggest a protective effect of skin awareness and self-examination, ^58,59 but final results from this study have not yet been published.

Primary prevention of skin cancer may involve limiting exposure to solar radiation (by limiting sun exposure, avoiding tanning facilities, and wearing protective clothing) or applying sunscreen preparations. Although the effectiveness of these maneuvers has not been evaluated in clinical trials, avoiding sun exposure or using protective clothing is likely to decrease the risk of MM and NMSC, since both types of cancer have been associated with sun exposure in numerous cohort and case-control studies. ^{3,4,17,19,20,25-27} Use of tanning facilities has not been directly linked to cancer risk, but skin damage after use is common. ^60,61 Many adolescents report using such facilities, ⁶¹ and severe sunburns occurring at a young age may increase the risk of subsequent melanoma. ^{17,19,20,26,27} The principal adverse effect associated with avoiding exposure to ultraviolet and other solar radiation is failure to acquire a suntan, which may be perceived as undesirable by some. ^48,62,63

The evidence that sunscreens prevent skin cancer is less clear. Sunscreen agents are formulated and tested for their ability to prevent the acute effects of solar ultraviolet radiation (i.e., sunburn). ⁶⁴ Most currently available sunscreens block ultraviolet B (UVB) wavelengths, and a few block ultraviolet A (UVA) rays. ⁶⁵ Only the physical sunblocks (e.g., zinc oxide, talc, etc.) block all solar rays. A randomized controlled trial evaluated the regular use of UVA- and UVB-blocking sunscreens by persons >=40 years of age with previous solar keratoses (which are precursors of SCC, although their risk of malignant transformation is low). ⁶⁶ The development of solar keratoses over a 6-month period was significantly reduced, implying that the risk of SCC may also be reduced. The generalizability of the results achieved by these highly motivated volunteers is unknown, and the study did not adequately describe investigator blinding, lesion classification, or the adequacy of randomization. Studies in albino laboratory rodents have also reported that sunscreens can reduce the incidence of tumors resembling human SCC after UV radiation. ^64,67-69 Animal data are more limited for MM, but a recent study in mice reported that sunscreen failed to protect against UV radiation-induced increases in melanoma incidence, although it did prevent sunburn. ⁷⁰ In a fish model, both UVA and visible light, which are not blocked by many currently available sunscreens, were highly effective in inducing melanomas. ⁷¹ Several case-control and cohort studies found either no effect or a significantly increased risk of BCC ⁷² and MM ^73,74 in sunscreen users, after adjusting their risk estimates for phenotype (e.g., hair color, tendency to sunburn). The increased risk found in several of these studies may be due to residual confounding, since in all studies adjustment for phenotype reduced the crude risk estimates. It is also possible that sunscreens may increase skin cancer risk by encouraging susceptible persons to prolong exposure of greater skin surface areas to solar rays that are not blocked by most currently used sunscreens. There is as yet no direct evidence that sunscreens prevent skin cancer in humans, but clinical trials of sunscreen in humans are unlikely to be conducted due to cost and time constraints. Sunscreens are associated with mild to moderate side effects in 1-2% of users, including contact and photocontact dermatitis, contact urticaria, and comedogenicity, although these are readily reversible when use is discontinued. ^65,75,76

There are few data examining the effectiveness of counseling patients to protect themselves from sunlight. A case series evaluating counseling given at the time of removal of a skin cancer, and on a yearly basis thereafter, reported increased use of protective clothing and sunscreen and reduced deliberate tanning at 2-6-year follow-up. ⁷⁷ This study included only the two-thirds of patients who complied with follow-up and was not able to determine how much of the effect seen was due to the surgery alone. There is also evidence from case series that public education can increase knowledge and beliefs about the health risks of sun exposure, ^48,78 but cross-sectional surveys give conflicting results about whether knowledgeable persons act on this information. ^62,63,79 Community and worksite educational interventions to reduce the risk of skin cancer, including one with a concurrent control group, have demonstrated significantly increased use of sun protection measures, such as hats, shirts, and staying in the shade, after the intervention. ^80,81 Whether the results of such educational interventions can be generalized to clinician counseling is not known. No studies on the effectiveness of counseling in reducing skin cancer incidence or mortality were found.

The American Cancer Society recommends monthly skin self-examination for all adults ⁸ and physician skin examination every 3 years in persons 20-39 years old and annually in persons >= 40 years old. ⁸² The American Academy of Dermatology, ^2,83 and a National Institutes of Health (NIH) Consensus Panel ⁸⁴ recommend regular screening visits for skin cancer and patient education concerning periodic skin self-examinations. The NIH Consensus Panel also recommended that some family members of patients with MM be enrolled in surveillance programs. ⁸⁴ The Canadian Task Force on the Periodic Health Examination does not recommend for or against routine screening for skin cancer or periodic skin self-examination, but suggests that TSE for a very select subgroup of individuals at high risk (e.g., those with familial atypical mole and melanoma syndrome) may be prudent. ⁸⁵ The American Academy of Family Physicians recommends complete skin examination for adolescents and adults with increased recreational or occupational exposure to sunlight, a family or personal history of skin cancer, or evidence of precursor lesions these recommendations are under review. ⁸⁶ The American Cancer Society, ⁸ the American Academy of Dermatology, ^2,83 the American Medical Association, ⁸⁷ and the NIH Consensus Panel ⁸⁴ all recommend patient education concerning sun avoidance and sunscreen use. The American Academy of Family Physicians recommends skin protection from ultraviolet light for all persons with increased exposure to sunlight. ⁸⁶ The Canadian Task Force recommends avoidance of sun exposure and use of protective clothing, but it does not recommend either for or against sunscreen use for the prevention of skin cancer. ⁸⁵ The American Academy of Dermatology, ⁸⁸ the American Medical Association, ⁸⁷ the American Cancer Society, ⁸⁹ and the NIH Consensus Panel ⁸⁴ have recommended avoiding artificial tanning devices.

Basal cell and squamous cell skin carcinomas are very common but are slow-growing and rarely metastasize. It is unlikely that population screening would substantially improve the already excellent outcome of persons with these tumors. The principal potential benefit of periodic skin examination lies in discovering early MM. The sensitivity and specificity of skin examination by primary physicians, and the optimal frequency of such examinations, is unknown, however. MM is, in addition, uncommon in the general population (lifetime risk of about 1.0%). ⁹⁰ Since 99% of patients who would be examined annually under a policy of routine screening would never have MM, it is also important to consider the potential adverse effects as well as the cost/benefit ratio of skin cancer screening. Neither of these has been adequately evaluated. ^33,39 No controlled studies have demonstrated that screening for MM by primary providers improves outcome, although a time series study suggests a possible mortality benefit. There is thus weak evidence that screening by primary clinicians is effective in improving clinical outcome. In persons at very high risk for MM (i.e., those with melanocytic precursor or marker lesions), referral to skin cancer specialists for evaluation may be justified based on high burden of suffering, minimal adverse effects of TSE, and greater accuracy of the TSE by such specialists however, there is no direct evidence that screening this population reduces mortality. There is currently only limited evidence of the efficacy of skin self-examination in reducing melanoma mortality, but preliminary results from a population-based case-control study appear promising.

There is fair evidence of the efficacy and safety of sun avoidance and use of protective clothing for the prevention of skin cancer, and weaker evidence to support avoiding artificial tanning devices. There is also fair evidence from one randomized controlled trial, supported by animal data, that sunscreens that block UVA and UVB rays are efficacious in preventing squamous cell cancer precursors, but data are limited on the efficacy of sunscreens in preventing skin cancer. There is also good evidence of mild, reversible adverse effects of sunscreens. Community or worksite educational interventions may increase the use of these sun protection measures, but the effectiveness of clinician counseling in modifying such behaviors is not established.

CLINICAL INTERVENTION

There is insufficient evidence to recommend for or against routine screening for skin cancer by primary care providers using total-body skin examination ("C" recommendation). Clinicians should remain alert for skin lesions with malignant features (i.e., asymmetry, border="1" irregularity, color variability, diameter > 6 mm, or rapidly changing lesions) ⁸⁴ when examining patients for other reasons, particularly patients with established risk factors. Such risk factors include clinical evidence of melanocytic precursor or marker lesions (e.g., atypical moles, certain congenital moles), large numbers of common moles, immunosuppression, a family or personal history of skin cancer, substantial cumulative lifetime sun exposure, intermittent intense sun exposure or severe sunburns in childhood, freckles, poor tanning ability, and light skin, hair, and eye color. Appropriate biopsy specimens should be taken of suspicious lesions.

Persons with melanocytic precursor or marker lesions (e.g., atypical moles [also called dysplastic nevi], certain congenital nevi, familial atypical mole and melanoma syndrome) are at substantially increased risk for MM. A recommendation to consider referring these patients to skin cancer specialists for evaluation and surveillance may be made on the grounds of patient preference or anxiety due to high burden of suffering, the greater accuracy of TSE when performed by such specialists, and the relatively limited adverse effects from TSE and follow-up skin biopsy, although evidence of benefit from such referral is lacking.

There is also insufficient evidence to recommend for or against counseling patients to perform periodic self-examination of the skin ("C" recommendation). Clinicians may wish to educate patients with established risk factors for skin cancer (see above) concerning signs and symptoms suggesting cutaneous malignancy and the possible benefits of periodic self-examination.

Avoidance of sun exposure, especially between the hours of 10:00 am and 3:00 pm, ⁶⁵ and the use of protective clothing such as shirts and hats when outdoors are recommended for adults and children at increased risk of skin cancer (see above) ("B" recommendation). Counseling such patients to avoid excess sun exposure and use protective clothing is recommended, based on the established efficacy of risk reduction from sun avoidance, the potential for large health benefits, low cost, and low risk of adverse effects from such counseling, even though the effectiveness of such counseling is less well established ("C" recommendation).

There is insufficient evidence to recommend for or against counseling patients to use sunscreens to prevent skin cancer ("C" recommendation). The routine use of sunscreens that block both UVA and UVB radiation may be appropriate for persons who have previously had solar keratosis and who cannot avoid sun exposure, in order to prevent additional solar keratoses, which have a small malignant potential.

The draft update of this chapter was prepared for the U.S. Preventive Services Task Force by Carolyn DiGuiseppi, MD, MPH.

Testicular cancer is a relatively uncommon disease, with an overall annual incidence of about 4/100,000 men. ¹ It is, however, the most common form of cancer in young men between ages 20 and 35, ² accounting for an estimated 7,100 new cases and 370 deaths in the U.S. in 1995. ³ The peak annual incidence ranges from 8 to 14/100,000 men between 20 and 35 years of age, with a smaller peak in early childhood. ⁴ The incidence in black men is less than one fifth that of white men. ⁴ The major predisposing risk factor is cryptorchidism. ¹ In men with a history of cryptorchidism, 80-85% of testicular tumors occur in the cryptorchid testicle, while 15-20% occur in the contralateral testicle. Other risk factors include previous cancer in the other testicle, a history of mumps orchitis, inguinal hernia, or hydrocele in childhood, and high socioeconomic status. ¹

Ninety-six percent of testicular cancers are of germ cell origin, of which seminoma is the most common type. Prognosis and treatment depend on the cell type and stage of disease however, recent advances in treatment have resulted in a 92% overall 5-year survival. ³ Even among the small proportion of patients (12%) with advanced disease at diagnosis, 5-year survival is close to 70%. ⁴

The two screening tests proposed for testicular cancer are physician palpation of the testes and self-examination of the testes by the patient. Detection of a suspicious testicular mass constitutes a positive test, and the diagnosis is confirmed by biopsy and histologic examination of tissue. There is no information on the sensitivity, specificity, or positive predictive value of testicular examination in asymptomatic persons whether done by providers or by patients. Even if they were known, measures of sensitivity and specificity for palpation of the testes might not be very meaningful because of the low incidence of testicular cancer and the high cure rate. If sensitivity is defined as the probability that disease, when present, is detected at a curable stage, then sensitivity is probably high because the overall cure rate (in the absence of systematic screening) is 92%. The negative predictive value is probably also quite good due to the low incidence of the disease. The positive predictive value, however, of palpation of the testes is probably very low due to the low incidence of disease and large number of other causes of scrotal masses.

There is evidence from older literature that between 26% and 56% of patients presenting initially to their physician with testicular cancer are first diagnosed as having epididymitis, testicular trauma, hydrocele, or other benign disorders, ^6-8 and these patients often receive treatment for these conditions before the cancer is diagnosed. ^7,9,10

There have been few studies of whether counseling men to perform self-examination motivates them to adopt this practice or to perform it correctly. Research to date has demonstrated only that education about testicular cancer and self-examination may enhance knowledge and self-reported claims of performing testicular examination. ^11,12 One study found that men who reviewed an educational checklist on how to perform self-examination were able to demonstrate greater skill when self-examination was performed moments later they were also able to recall the contents of the checklist in a telephone survey months later. ¹³ Few studies, however, have examined whether education or self-examination instructions actually increase the performance of self-examination. It is also unclear whether persons who detect testicular abnormalities seek medical attention promptly. Patients with testicular symptoms may wait as long as several months before contacting a physician. ⁶

Finally, no studies have been conducted to test whether persons who perform testicular self-examination are more likely to detect early-stage tumors or have better survival than those who do not practice self-examination. ⁵ Published evidence that self-examination can detect testicular cancer in asymptomatic persons is limited to a small number of case reports. ¹⁴

Tumor markers, including alpha-fetoprotein and human chorionic gonadotropin are useful in following nonseminomatous testicular cancers but are not useful for early detection or screening. ^1,15

The prognosis for advanced stages of testicular cancer has improved dramatically in the past decade with the introduction of better chemotherapy. Current cure rates are greater than 80%. ^5,16 Survival, however, is still better for patients with Stage I cancer than in those with more advanced disease, and the treatment of early cancer has less cost and morbidity. Treatment for all types and stages of testicular cancer includes removal of the involved testicle. The current 5-year survival for Stage I seminoma treated with radiotherapy is 97%. ³ Stage I nonseminomatous cancers (e.g., teratoma, embryonal carcinoma, choriocarcinoma) treated with radical retroperitoneal lymph node dissection have a reported 3-5-year survival approaching 90%. ¹⁷ With the advent of cisplatin-based chemotherapeutic regimens, a 3-year survival of 90-100% has been reported. Reported survival in patients with disseminated testicular cancer, however, is lower (about 67-80%), and these persons require intensive treatment with chemotherapeutic agents that produce a variety of systemic side effects. ^3,5,16

Although lead-time and length biases may account for part of the improved survival observed for persons with early-stage testicular cancer, it is likely that the prognosis is better for persons with less advanced disease. No studies have been done to determine whether screening increases the proportion of cancers diagnosed at early stages, or improves outcomes. Even without screening, 60-80% of seminomas are Stage I at diagnosis. ¹⁷ There is evidence that once testicular symptoms have appeared, diagnostic delays are associated with more advanced disease and lower survival. ^6,7,18

The appropriate management and follow-up of patients with a history of an undescended testicle is controversial. ^19,20 It is known that orchiopexy at puberty does not reduce malignant transformation. It is uncertain whether earlier orchiopexy prior to school age, which is now common practice, will prevent development of testicular cancer. ¹⁹ Giwercman et al. found carcinoma in situ in 2% of men with a history of cryptorchidism who had testicular biopsies. ²⁰ They predicted 50% of these lesions would progress to invasive cancer and recommended that testicular biopsy be offered to all men with a history of cryptorchidism. Many experts recommend that intraabdominal testes should be removed. ¹ The survival for patients with a history of cryptorchidism who develop testicular cancer is excellent, as it is in noncryptorchid patients. No studies have been done to evaluate benefits of formal screening of men with a history of cryptorchidism.

The American Cancer Society recommends a cancer checkup that includes testicular examination every 3 years for men over 20 and annually for those over 40. ²¹ No recommendation is given for testicular self-examination. The American Academy of Family Physicians recommends a clinical testicular examination for men aged 13-39 years who have a history of cryptorchidism, orchiopexy, or testicular atrophy this policy is currently under review. ²² The American Academy of Pediatrics recommends testes self-examination beginning at age 18 years. ²³ The Canadian Task Force on the Periodic Health Examination concluded that there is insufficient evidence to include or exclude routine screening for testicular cancer by palpation in the periodic health examination. ²⁴

There is no direct experimental evidence on which to base a recommendation for or against screening for testicular cancer by either physician examination or patient self-examination, since no studies of screening have been done. It seems unlikely that screening would substantially improve the already favorable outcome in this uncommon disease. If a population of 100,000 men aged 15-35 years were screened with a 100% sensitive test, at most 10 cancers would be detected. At least nine of these would be expected to be cured in the absence of a formal screening program. It is unknown whether the tenth patient would also be cured as a result of the cancer being detected by screening. A primary care physician with 1,500 males in his/her practice could expect to detect one testicular cancer every 15-20 years. The vast majority of men screened by either physician or self-palpation would have normal examinations of those with suspicious masses, most would have benign disease (false positives). Many of these cases, however, would require referral to urologists, radiographic studies, or invasive procedures (e.g., biopsy or inguinal exploration) before malignancy could be ruled out. ¹⁷ These interventions would incur considerable costs and possible morbidity.

Men with a history of undescended testes or testicular atrophy have a much greater incidence of testicular cancer. Although screening in this population has also not been shown to improve outcome, it would be expected to have a much higher yield than screening in the general population.

CLINICAL INTERVENTION

There is insufficient evidence to recommend for or against routine screening of asymptomatic men for testicular cancer by physician examination or patient self-examination ("C" recommendation). Patients with an increased risk of testicular cancer (those with a history of cryptorchidism or atrophic testes) should be informed of their increased risk of testicular cancer and counseled about the options for screening. Such patients may then elect to be screened or to perform testicular self-examination. Adolescent and young adult males should be advised to seek prompt medical attention if they notice a scrotal abnormality.

The draft update of this chapter was prepared for the U.S. Preventive Services Task Force by Paul S. Frame, MD.

Ovarian cancer is the fifth leading cause of cancer deaths among U.S. women and has the highest mortality of any of the gynecologic cancers. ¹ It accounted for an estimated 26,600 new cases and 14,500 deaths in 1995. ¹ The lifetime risk of dying from ovarian cancer is 1.1%. ^1a The overall 5-year survival rate is at least 75% if the cancer is confined to the ovaries and decreases to 17% in women diagnosed with distant metastases. ^2,3 Symptoms usually do not become apparent until the tumor compresses or invades adjacent structures, ascites develops, or metastases become clinically evident. ⁴ As a result, two thirds of women with ovarian cancer have advanced (Stage III or IV) disease at the time of diagnosis. ^2,5,6 Carcinoma of the ovary is most common in women over age 60. ⁷ Other important risk factors include low parity and a family history of ovarian cancer. ^8-10 Less than 0.1% of women are affected by hereditary ovarian cancer syndrome, but these women may face a 40% lifetime risk of developing ovarian cancer. ¹¹

Potential screening tests for ovarian cancer include the bimanual pelvic examination, the Papanicolaou (Pap) smear, tumor markers, and ultrasound imaging. The pelvic examination, which can detect a variety of gynecologic disorders, is of unknown sensitivity in detecting ovarian cancer. Although pelvic examinations can occasionally detect ovarian cancer, ^12,13 small, early-stage ovarian tumors are often not detected by palpation, ^14,15 due to the deep anatomic location of the ovary. Thus, ovarian cancers detected by pelvic examination are generally advanced ^7,16-18 and associated with poor survival. ¹⁶ The pelvic examination may also produce false positives when benign adnexal masses (e.g., functional cysts) are found. ^16,19 The Pap smear may occasionally reveal malignant ovarian cells, ²⁰ but it is not considered a valid screening test for ovarian carcinoma. ^16-18,21 Studies indicate that the Pap smear has a sensitivity for ovarian cancer of only 10-30%. ¹⁶

Serum tumor markers are often elevated in women with ovarian cancer. Examples of these markers include carcinoembryonic antigen, ovarian cystadenocarcinoma antigen, lipid-associated sialic acid, NB/70K, TAG 72.3, CA15-3, and CA-125. CA-125 is elevated in 82% of women with advanced (Stage III or IV) ovarian cancer, ²² and it is also elevated, although less frequently, in women with earlier stage disease. ²³ In studies of women with known or suspected ovarian cancer, the reported sensitivities of CA-125 in detecting Stage I and Stage II cancers are 29-75% and 67-100%, respectively. ^24-30 These cases may not be representative of asymptomatic women in the general population, however. In screening studies, including a recent study of more than 22,000 women, the reported sensitivity was 53-85%. ^13,31 Evidence is limited on whether tumor markers become elevated early enough in the natural history of occult ovarian cancer to provide adequate sensitivity for screening. Studies of stored sera have found that about one half of women who developed ovarian cancer had elevated CA-125 levels (>35 U/mL) 18 months ²³ to 3 years ³² before their diagnosis. Further research is needed, however, to provide more reliable data on the sensitivity of this and other tumor markers in detecting early-stage ovarian cancer in asymptomatic women.

Tumor markers may have limited specificity. It has been reported that CA-125 is elevated in 1% of healthy women, 6-40% of women with benign masses (e.g., uterine fibroids, endometriosis, pancreatic pseudocyst, pulmonary hamartoma), and 29% of women with nongynecologic cancers (e.g., pancreas, stomach, colon, breast). ^22,33 Reported specificity in screening studies is about 99%. ^13,31 It may be possible to improve the specificity of CA-125 measurement by selective screening of postmenopausal women, ³⁴ modifying the assay technique, ³⁵ adding other tumor markers to CA-125, ³⁶ requiring a higher concentration or persistent elevation of CA-125 levels over time, or combining CA-125 measurement with ultrasound (see below). Prospective studies involving asymptomatic women are needed, however, to provide definitive data on the performance characteristics of these techniques when used as screening tests.

Ultrasound imaging has also been evaluated as a screening test for ovarian cancer, since it is able to estimate ovarian size, detect masses as small as 1 cm, and distinguish solid lesions from cysts. ^17,37 Transvaginal color-flow Doppler ultrasound can also identify vascular patterns associated with tumors. ^38,39 In screening studies, the reported sensitivity and specificity of transabdominal or transvaginal ultrasound are 50-100% and 76-97%, respectively, ^{3,14,15,40-43} but small sample sizes, limited follow-up, and outdated techniques may limit the validity of the data. Studies have shown that routine ultrasound testing of asymptomatic women has a low yield in detecting ovarian cancer and generates a large proportion of false-positive results that often require diagnostic laparotomy or laparoscopy. In one study, ultrasound screening of 805 high-risk women led to 39 laparotomies, which revealed one ovarian carcinoma, two borderline tumors, one cancer of the cecum, and five cystadenomas. ⁴⁰ A transvaginal ultrasound study of 600 patients with previous breast cancer revealed 18 patients with complex cysts or enlarged ovaries. Laparotomy was performed on 21 patients, four of whom had ovarian cancer (positive predictive value of 22%) the use of color-flow imaging appeared to increase the positive predictive value. ⁴⁴

In a larger study, ultrasound was performed routinely on 5,678 asymptomatic female volunteers over age 45 or with a history of previous breast or gynecologic cancer. ^44a Two Stage I ovarian cancers were detected in a total of 6,920 scans performed over 2 years. Another report from the same center indicated that 14,356 ultrasound examinations performed over 3 years on 5,489 asymptomatic women over age 45 detected five ovarian cancers. ⁴⁵ Although the sensitivity and specificity of the test were excellent (100% and 94.6%, respectively), the positive predictive value in this low-risk study population was only 2.6% and follow-up was of short duration. It has been calculated from these results and other data that ultrasound screening of 100,000 women over age 45 would detect 40 cases of ovarian cancer, but at a cost of 5,398 false positives and over 160 complications from diagnostic laparoscopy. ⁴⁶

It may be possible to improve accuracy by combining ultrasound with other screening tests, such as the measurement of CA-125. This approach has been examined as a method of discriminating between benign and malignant adnexal masses in preoperative patients. ⁴⁷ Further research is needed, however, to determine the sensitivity, specificity, and positive predictive value of performing these tests in combination to screen asymptomatic women. One prospective study ¹² screened 1,010 asymptomatic postmenopausal women over age 45 with pelvic examination and CA-125 measurement those with abnormal results received an ultrasound examination. Although one ovarian cancer was detected (all three screening tests were positive in this woman), the study demonstrated poor positive predictive value with each of the three screening tests. No abnormality was discovered in 28 of the 31 women with elevated CA-125. Fibroids and benign cysts were responsible for over half of the 28 abnormal pelvic examinations. There were 13 abnormal ultrasound examinations 12 of these women consented to laparotomy, which revealed six benign ovarian cysts, two fimbrial cysts, two women with no surgical findings, one woman with adhesions, and the ovarian cancer. A more recent report from the same center found that the combination of abdominal ultrasound and sequential CA-125 measurements had a sensitivity of 58-79%, a specificity of about 100%, and a positive predictive value of 27%. ³¹ Another program that screened 597 women with transvaginal color-flow Doppler ultrasound and CA-125 measurements detected abnormalities in 115 patients, only one of whom had ovarian cancer. ⁴⁸

There is no direct evidence from prospective studies that women with early-stage ovarian cancer detected through screening have lower mortality from ovarian cancer than do women with more advanced disease. A large body of indirect evidence, however, suggests that this is the case. Although lead-time and length biases may be responsible, it is known that survival from ovarian cancer is related to stage at diagnosis. The 5-year survival rate is 89% for localized disease, 36% for women with regional metastases, and 17% for women with distant metastases. ¹ Studies have shown that the most important prognostic factor in patients with advanced ovarian cancer is the size of residual tumor after treatment. ^4,7 Surgical debulking and chemotherapy for ovarian cancer appear to be more effective in reducing the size of residual tumor when ovarian cancer is detected early. ⁴ Although these observations provide suggestive evidence that early detection may be beneficial, conclusive proof will require properly conducted prospective studies comparing long-term mortality from ovarian cancer between screened and nonscreened cohorts. A large clinical trial to obtain this evidence has recently been launched by the National Cancer Institute. ⁴⁹ Under the most optimistic assumptions (100% sensitivity, 30% reduction in 5-year mortality with screening, no lead-time bias), annual pelvic examinations of 40-year-old women would reduce 5-year mortality from ovarian cancer in the population by less than 0.0001%. ⁵⁰ Modeling studies that have examined annual CA-125 testing or a single screening with transvaginal ultrasound and CA-125 measurement have found that either approach would increase life expectancy by an average of less than 1 day per woman screened. ^51,52

There are no official recommendations to screen routinely for ovarian cancer in asymptomatic women by performing ultrasound or serum tumor marker measurements. The American College of Physicians (ACP), ⁵³ the Canadian Task Force on the Periodic Health Examination, ⁵⁴ and the American College of Obstetricians and Gynecologists ⁵⁵ recommend against such screening. A National Institutes of Health Consensus Conference on Ovarian Cancer recommended taking a careful family history and performing an annual pelvic examination on all women. ⁵⁶ The pelvic examination, including palpation of the adnexae, is mentioned in a recommendation on Pap testing issued by the American Cancer Society, National Cancer Institute, American College of Obstetricians and Gynecologists, American Medical Association, American Nurses Association, American Academy of Family Physicians, and the American Medical Women's Association. ⁵⁷ Specifically, the pelvic examination (and Pap smear) is recommended annually for all women who are or have been sexually active or have reached age 18. Although Pap testing may be performed less frequently once three annual smears have been normal, the American Cancer Society specifies that the pelvic examination be performed with the Pap test every 1-3 years in women aged 18-40 years and annually thereafter. ⁵⁸

The NIH Consensus Conference concluded that women with presumed hereditary cancer syndrome should undergo annual pelvic examinations, CA-125 measurements, and transvaginal ultrasound until childbearing is completed or at age 35, at which time prophylactic bilateral oopherectomy was recommended. ⁵⁶ The ACP recommends counseling high-risk women about the potential benefits and harms of screening. ⁵³ The Canadian Task Force on the Periodic Health Examination found insufficient evidence to recommend for or against screening for ovarian cancer in high-risk women. ⁵⁴

The sensitivity and specificity of available screening tests for ovarian cancer in asymptomatic women are uncertain and require further study. Although various tests can detect occasional asymptomatic tumors, there is currently no evidence that routine screening will improve overall health outcomes. The large majority of women with abnormal screening test results do not have cancer, yet will require invasive procedures (laparoscopy or laparotomy) to rule out malignancy. Given the risks, inconvenience, and substantial costs of follow-up testing, and the current lack of evidence that screening reduces morbidity or mortality from ovarian cancer, routine screening cannot be recommended. Trials to determine the benefits and risks of ovarian cancer screening are under way. There is also no evidence to support routine screening in women with a history of ovarian cancer in a first-degree relative. Although such women are at increased risk and stand to benefit more from interventions that reduce ovarian cancer mortality, the effectiveness of screening has yet to be determined for any group of women. Referral to a specialist may be appropriate for women whose family history suggests hereditary ovarian cancer syndrome, due to the very high risk of cancer in this disorder.

CLINICAL INTERVENTION

Screening asymptomatic women for ovarian cancer with ultrasound, the measurement of serum tumor markers, or pelvic examination is not recommended ("D" recommendation). There is insufficient evidence to recommend for or against the screening of asymptomatic women at increased risk of ovarian cancer ("C" recommendation).

The draft update of this chapter was prepared for the U.S. Preventive Services Task Force by Steven H. Woolf, MD, MPH, based in part on a paper prepared for the Clinical Efficacy Assessment Panel of the American College of Physicians by Karen J. Carlson, MD, et al. See relevant background paper: Carlson KJ, Skates SJ, Singer DE. Screening for ovarian cancer. Ann Intern Med 1994121:124-132.

Cancer of the pancreas is the fifth leading cause of cancer deaths in the U.S., accounting for an estimated 27,000 deaths in 1995 (8.4 deaths/100,000 persons). ^1,1a Worldwide, the age-adjusted incidence and mortality of pancreatic cancer have been increasing since the 1930s, ^2,3 although in the U.S. these rates have declined since the early 1970s. ^1,1a Incidence rates may be overestimated, because an important proportion of pancreatic cancer diagnoses (as many as half in some studies) are not histologically confirmed. ⁴ Pancreatic cancer is more common in men, blacks, cigarette smokers, and older persons (the majority of cases being diagnosed between ages 65 and 79). ^1,2,3,5 The risk of pancreatic cancer is increased in patients with diabetes, including those with long-standing (>=5 years) diabetes. ^5a Familial aggregations of pancreatic cancer are rare but have been described. ^2,6

Since initial symptoms are usually nonspecific (e.g., abdominal pain and weight loss) and are frequently disregarded, some 80-90% of patients have regional and distant metastases by the time they are diagnosed. ^5,7 Only 3% of the 24,000 patients annually diagnosed with pancreatic cancer live more than 5 years after diagnosis. ^1,1a Of pancreatic adenocarcinomas, which account for more than 90% of all pancreatic neoplasms, ⁵ only about 4-16% are resectable at diagnosis, ^4,8-12 and the 5-year survival rate is less than 1%. ⁷ In addition, 5-year survival does not indicate cure, since further decrements in survival occur after 5 years. ^13,14

Adenocarcinoma is the principal form of pancreatic neoplasm for which screening has been considered in this chapter, "pancreatic cancer" refers to adenocarcinoma. There are no reliable screening tests for detecting pancreatic cancer in asymptomatic persons. The deep anatomic location of the pancreas makes detection of small localized tumors unlikely during the routine abdominal examination. Even in patients with confirmed pancreatic cancer, an abdominal mass is palpable in only 15-25% of cases. ^4,5,15,16

Imaging procedures such as magnetic resonance imaging and computed tomography are too costly to use as routine screening tests, while more accurate tests such as endoscopic retrograde cholangiopancreatography and endoscopic ultrasound are inappropriate for screening asymptomatic patients due to their invasiveness. ^17,18 Abdominal ultrasonography is a noninvasive screening test, but there is little information on the efficacy of abdominal ultrasound as a screening test for pancreatic cancer in asymptomatic persons. In symptomatic patients with suspected disease it has a reported sensitivity of 40-98% and a specificity as high as 90-94%. ^15,19,20 Conventional ultrasonography is limited by visualization difficulties in the presence of bowel gas or obesity and by its range of resolution (2-3 cm). ^7,18,20 Even tumors <2 cm in diameter are frequently associated with metastatic disease, ^8,11,21 thus limiting the ability of ultrasound to detect early disease.

Most persons with pancreatic malignancy have elevated levels of certain serologic markers such as CA19-9, peanut agglutinin, pancreatic oncofetal antigen, DU-PAN-2, carcinoembryonic antigen, alpha-fetoprotein, CA-50, SPan-1, and tissue polypeptide antigen. ^22-25 None of these markers is, however, tumor specific or organ specific ²⁵ elevations of various serologic markers also occur in significant proportions of persons with benign gastrointestinal diseases or malignancies other than pancreatic cancer. ^17,22,24,25 Most of these markers have been studied exclusively in high-risk populations, such as symptomatic patients with suspected pancreatic cancer. CA19-9 has probably achieved the widest acceptance as a serodiagnostic test for pancreatic carcinoma in symptomatic patients, with an overall sensitivity of approximately 80% (68-93%) and specificity of 90% (73-100%) sensitivity was highest in patients with more advanced disease. ^23,24 Among healthy subjects, CA19-9 has good specificity (94-99%) ^26-28 but nevertheless generates a large proportion of false-positive results due to the very low prevalence of pancreatic cancer in the general population. ²⁹ A study of a mass screening of more than 10,000 asymptomatic persons for pancreatic cancer in Japan, ³⁰ using either ultrasonography alone or CA19-9 plus elastase-1, found the likelihood of pancreatic cancer given a positive screening test to be 0.5% only one of the four cancers discovered could be curably resected.

The predictive value of a positive test could be improved if a population at substantially higher risk could be identified. Diabetes mellitus in older adult patients might be useful as a marker for a population at high risk of having pancreatic cancer. ^3,31,32 Cohort studies have reported incidences of pancreatic cancer among diabetic patients ranging from 51 to 166/100,000 person-years. ^5a Studies evaluating screening efficacy might therefore be warranted in this population.

Evidence that early detection can lower morbidity or mortality from pancreatic cancer is not conclusive. The reported 5-year survival for localized disease based on 1983-1990 national data is only 9%, not substantially higher than the 5-year survival with regional (4%) and distant (2%) metastases. ^1a A comprehensive review of published reports on surgical resection of pancreatic cancer estimated an overall 5-year survival rate of 8% for small tumors without evidence of local or distant spread. ⁸ In part, this low rate may reflect the fact that a proportion of patients with localized disease cannot be operated on because of concomitant medical problems, advanced age, or other reasons. ^10,11,13 Patients who have small localized tumors that are resected for attempted cure, which account for only 4-16% of the total, may have better 5-year survival rates (as high as 37-48% in the most experienced centers), ^8-13,21,33 although the designs of most studies of surgical outcome suffer from lead-time, length, and selection biases. The morbidity associated with surgical resection is high (15-53%), but perioperative mortality is now less than 7% in the hands of experienced surgeons. ^8,9,13,33,34

Reports on the effectiveness of adjuvant external beam and/or intraoperative radiotherapy in improving survival among curatively resected patients, using historical controls, have yielded inconsistent results. ^35-37 In one small randomized controlled trial, ³⁸ corroborated by a subsequent case series by the same authors, ³⁹ an adjuvant treatment program using combined radiation and chemotherapy following curative resection was associated with a significant median survival advantage of 9 months and a 5-year survival advantage of 14.5% in treated versus control cases however, the study was closed early due to poor subject accrual and it did not control for the substantially greater frequency of clinic visits by cases. Adverse effects of combined radiation and chemotherapy include leukopenia and gastrointestinal toxicity. ^38,40 Intraoperative radiotherapy frequently causes gastrointestinal bleeding, which may be life-threatening. ³⁷ Additional randomized controlled trials of adjuvant therapy are needed to confirm its effectiveness in improving survival in patients with early pancreatic carcinoma. New modalities being explored include immunotherapy ⁴¹ and hormonal therapy. ⁴²

Cigarette smoking has been consistently associated with a modestly increased risk of pancreatic cancer in numerous cohort and case-control studies of populations in the U.S., Canada, Europe, and Japan. ^3,43-46 A clear dose-response relationship has not been demonstrated, however, nor have the biologic mechanisms underlying this association been adequately delineated. Cohort and case-control studies suggest that former smokers have a decreased risk of pancreatic cancer compared with current smokers, ^43,44,47-49 but estimates of the duration of abstinence required to show a reduction in risk have varied from as few as 1-3 years to as many as 10-20 years, and some studies have found no risk reduction at all associated with smoking cessation. ^43,45 In addition, a number of these studies suffer from selection, misclassification, and other biases. Although the causal relationship between smoking and pancreatic cancer requires further study, counseling patients to discontinue smoking (see Chapter 54) is easily justified by its established efficacy in preventing other malignancies (e.g., lung cancer), coronary artery disease, and other serious disorders.

Several cohort studies and many population-based case-control studies have reported positive associations between pancreatic cancer and dietary factors such as meat, eggs, carbohydrates, refined sugar, cholesterol, fat, and total calorie intake, as well as negative (protective) associations with intake of vegetables and fruits. ^{3,46,48,50-56} However, study results are inconsistent many studies suffer from selection, misclassification, and other biases and large numbers of comparisons make significance testing problematic. Further research to define nutritional risk factors for pancreatic cancer is therefore needed. Studies of the relationship between increased alcohol consumption and pancreatic cancer have yielded inconsistent results ^{3,45-48,57,58} few have adequately assessed level and duration of intake, or evaluated the possibility of a link between alcohol, pancreatitis, and pancreatic cancer. Current epidemiologic evidence does not support an association between pancreatic cancer and coffee consumption. ^3,58,59

No groups recommend routine screening for pancreatic cancer in asymptomatic persons. The Canadian Task Force on the Periodic Health Examination recommends against such screening. ⁶⁰

Given the lack of evidence for improved outcome with early detection of pancreatic cancer, the invasive nature of diagnostic tests likely to follow a positive screening test (e.g., endoscopic ultrasound, laparotomy), and the fact that most positive screening tests would be false positives, screening for pancreatic cancer cannot be recommended at this time. Primary prevention of pancreatic cancer may be possible through clinical efforts directed at the use of tobacco products.

CLINICAL INTERVENTION

Routine screening for pancreatic cancer in asymptomatic persons, using abdominal palpation, ultrasonography, or serologic markers, is not recommended ("D" recommendation). All patients should be counseled regarding use of tobacco products (see Chapter 54). Counseling to reduce fat and cholesterol intake and to increase intake of fruits and vegetables may be recommended on other grounds (see Chapter 56).

The draft update of this chapter was prepared for the U.S. Preventive Services Task Force by Carolyn DiGuiseppi, MD, MPH.

The term "oral cancer" includes a diverse group of tumors arising from the oral cavity. Usually included are cancers of the lip, tongue, pharynx, and oral cavity. The annual incidence of oral cancer in the U.S. is about 11/100,000 population, with a male/female ratio greater than 2:1. ¹ Oral cancer is responsible for 2% of all cancer deaths in the U.S., and it is projected to account for over 28,000 new cases and about 8,400 deaths in 1995. ²

Fifty-three percent of oral cancers have spread to regional or distant structures at the time of diagnosis. ¹ Overall 5-year survival is 52%, but it ranges from 79% for localized disease to 19% if distant metastases are present. ¹ The natural history of each type of cancer can be quite different. Cancer of the lip accounts for 11% of new cases of oral cancer but only 1% of deaths. In contrast, cancer of the pharynx accounts for 31% of new cases of oral cancer but 50% of deaths. ¹ The median age at diagnosis of oral cancers is 64 years, and 95% occur in persons over age 40. About half of all oropharyngeal cancers and the majority of deaths from this disease occur in persons over age 65. ¹

Use of tobacco in all forms and, to a lesser extent, alcohol abuse are the major risk factors for the development of oral cancer. ³ The risk of oral cancer is increased 6-28 times in current smokers, ⁴ and the effects of tobacco and alcohol account for 90% of oral cancer in the U.S. ⁵ In parts of India and Asia where chewing tobacco or betel nut is very common, the incidence of oral cancer is 3 times higher than in the U.S. ⁵ In several areas of India, oral cancer accounts for 40% of all female cancer deaths. ⁵ Other risk factors for oral cancer include occupational exposures, solar radiation (for cancer of the lip), and the presence of premalignant lesions such as leukoplakia or erythroplakia. ³ Depending on the degree of histologic abnormality, up to 18% of cases of leukoplakia may develop into invasive cancers over long-term follow-up. ⁵ Patients infected with human immunodeficiency virus are at increased risk of oral cancers, most commonly Kaposi's sarcoma and non-Hodgkin's lymphoma. ⁶

The principal screening test for oropharyngeal cancer in asymptomatic persons is inspection and palpation of the oral cavity. Studies indicate that many oral cancers occur on the floor of the mouth, the ventral and lateral regions of the tongue, and the soft palate, anatomic sites that may be inaccessible to routine visual inspection. ⁷ The recommended examination technique involves a careful visual examination of the oral cavity and extraoral areas using a dental mirror, retracting the tongue with a gauze pad to visualize hard-to-see areas. It also includes digital palpation with a gloved hand for masses. Complete descriptions of the recommended techniques have been published. ⁸ There is little information, however, on the sensitivity of this procedure in detecting oral cancer or on the frequency of false-positive results when a lesion is found. The abbreviated oral inspection that is more typical of the routine physical examination is also of unknown accuracy and predictive value. Studies in India and Sri Lanka have shown that nonphysician basic health care workers, given a short course on screening for oral cancer, can identify oral cancers and their precursors. ^9,10 Mehta found a 59% sensitivity and 98% specificity for lesions appropriately referred to dentists by the basic health care workers. ⁹ No outcome data were reported in these studies, and it is unclear how these findings relate to the very different, lower prevalence population of the United States.

Some studies suggest that dentists are more effective than are physicians in routinely performing a complete mouth examination and detecting early-stage oral cancer. ¹¹ Older Americans, the population at greatest risk for oral cancer, visit the dentist infrequently, however physician visits are much more frequent in older persons. ¹² No studies of the sensitivity and specificity of screening for oral cancer by dentists have been reported.

Alternative screening tests for oral cancer have been proposed, such as tolonium chloride rinses to stain suspicious lesions, ^13,14 but further research is needed to evaluate the accuracy and acceptability of these techniques before routine use in the general population can be considered.

No controlled trials of screening for oral cancer that include data on clinical outcomes have been reported. There is consistent evidence that persons with early-stage oral cancer have a better prognosis than those diagnosed with more advanced disease. ^1,2 Because of the possible effects of lead-time and length bias, however, these observational data are not sufficient to prove that screening and earlier detection improve the prognosis in patients with oral cancer. Some authors have questioned the effectiveness of early detection in improving prognosis. ¹⁵ Prospective trials of screening for oral cancer, although difficult and expensive to conduct in the general population, might be feasible in high-risk populations in which the incidence of oral cancer is substantially greater.

Several studies have examined treatment of oral leukoplakia, a form of premalignancy, as a means of preventing oral cancer. Primary treatment of oral leukoplakia and prevention of second primary lesions in patients with treated oral cancer have been studied in several randomized, placebo-controlled chemoprevention trials of high-dose isotretinoin (13-cis-retinoic acid). ^16-18 These studies demonstrated that isotretinoin was effective in promoting remission of leukoplakia and preventing the occurrence of second primary oral cancers. ¹⁷ Leukoplakia relapsed in a majority of cases within 3-6 months after discontinuation of therapy, however, and the rate of toxicity of treatment was high (mild to moderate side effects in up to 79% of patients). A trial of alternate maintenance therapies after isotretinoin induction for leukoplakia suggested that low-dose isotretinoin was more effective in maintaining remissions than beta-carotene and caused fewer side effects than high-dose therapy: 12% of participants experienced severe toxicity and 42% had moderate toxicity from low-dose isotretinoin, including dry skin, cheilitis, and conjunctivitis. ¹⁸

Uncontrolled trials using beta-carotene demonstrated variable reductions (up to 71%) in the occurrence of oral leukoplakia and mucosal dysplasia. ^19-21 In a randomized trial, however, the majority of patients with leukoplakia progressed during beta-carotene treatment. ¹⁸ Although side effects of beta-carotene are minimal, older male smokers who took beta-carotene for 5-8 years experienced slightly higher rates of lung cancer and overall mortality in a recently completed trial in Finland. ²² Research is currently in progress on alternative agents (e.g., vitamin E) and combinations of therapies. ²³

The American Cancer Society recommends a cancer checkup that includes oral examination every 3 years for persons over age 20 and annually for those over age 40. ²⁴ The Canadian Task Force on the Periodic Health Examination concluded that there was insufficient evidence to include or exclude screening for oral cancer in the periodic health examination of persons in the general population, but suggested that annual oral examination by a physician or dentist should be considered for persons over 60 with risk factors for oral cancer (e.g., smokers and regular drinkers). ²⁵ Although the National Institutes of Health no longer issue specific clinical guidelines regarding screening for oral cancer, both the National Cancer Institute and the National Institute of Dental Research support efforts to promote the early detection of oral cancers during routine dental examinations. ^8,26

Primary prevention strategies, such as counseling patients regarding the use of tobacco and alcohol, may have a greater impact on the morbidity and mortality associated with oral cancer than measures aimed at early detection. There is good evidence that tobacco use and excessive consumption of alcohol are both independent and synergistic risk factors for oral cancer. ³ Over 90% of oropharyngeal cancer deaths are associated with smoking. ⁵ In addition to smoking and alcohol, oral cancer is also associated with the use of snuff and chewing tobacco. ²⁷

Oral cancer is a relatively uncommon cancer in the United States. Even among high-risk groups such as smokers, oral cancer accounts for a relatively small proportion (<2%) of all deaths. ⁴ Available screening tests for oral cancer are limited to the physical examination of the mouth, a test of undetermined sensitivity, specificity, and positive predictive value. Despite the strong association between stage at diagnosis and survival, there are few controlled data to determine whether routine screening in the primary care setting leads to earlier diagnosis or reduced mortality from oral cancer. Given the significant morbidity and mortality associated with advanced oral cancer and its treatment, clinicians may wish to include careful examinations for oral cancer in asymptomatic persons at significantly increased risk for the disease (see Clinical Intervention) direct evidence of a benefit of screening in any group, however, is lacking. It is also appropriate to refer patients for regular visits to a dentist, for whom complete examination of the oral cavity is often more feasible (see Chapter 61).

CLINICAL INTERVENTION

There is insufficient evidence to recommend for or against routine screening of asymptomatic persons for oral cancer by primary care clinicians ("C" recommendation). Although direct evidence of a benefit is lacking, clinicians may wish to include an examination for cancerous and precancerous lesions of the oral cavity in the periodic health examination of persons who chew or smoke tobacco (or did so previously), older persons who drink regularly, and anyone with suspicious symptoms or lesions detected through self-examination. All patients, especially those at increased risk, should be advised to receive a complete dental examination on a regular basis (see Chapter 61). All adolescent and adult patients should be asked to describe their use of tobacco (Chapter 54) and alcohol (Chapter 52). Appropriate counseling should be offered to those persons who smoke cigarettes, pipes, or cigars, those who use chewing tobacco or snuff, and those who have evidence of alcohol abuse. Persons with increased exposure to sunlight should be advised to take protective measures when outdoors to protect their lips and skin from the harmful effects of ultraviolet rays (see Chapter 12).

The draft update of this chapter was prepared for the U.S. Preventive Services Task Force by Paul S. Frame, MD, based on materials prepared for the Canadian Task Force on the Periodic Health Examination by Carl Rosati, MD, FRCSC.

Bladder cancer is an important cause of morbidity and mortality in the U.S., primarily in older men. Over 50,000 new cases and over 11,000 deaths due to bladder cancer are predicted to occur in 1995 in the U.S. ¹ Risk rises steeply with age over half of all deaths from bladder cancer occur after age 70. The incidence of bladder cancer is 3-4 times higher in men than women, and roughly twice as high in white men compared to black men. ^2,3 Among white men, the annual incidence of bladder cancer after age 65 is approximately 2/1,000 persons (vs. 0.1/1,000 under 65), and the lifetime probability of developing cancer is over 3%. ³ The probability of dying from bladder cancer is much smaller, however -- less than 1%. Cigarette smoking markedly increases the risk for bladder cancer (relative risk among smokers vs. nonsmokers = 1.5-7) ^4,5 nearly half of all new cases of bladder cancer occur in current or former smokers. ² Occupational exposure to chemicals used in dye, leather, and tire and rubber industries has also been associated with increased risks of bladder cancer. ⁴ Despite initial reports, positive associations between bladder cancer and consumption of coffee or artificial sweeteners have not been confirmed. ^2,6,7

Early asymptomatic bladder cancer may be associated with occult bleeding (microscopic hematuria) or the presence of dysplastic cells in the urine. The definition of significant hematuria varies, but more than 3-5 red blood cells (RBCs) per high-powered field in microscopic analysis of the urine sediment is usually considered abnormal. ⁸ Urine dipsticks, which detect peroxidase activity of hemoglobin, provide a quick, inexpensive, and sensitive test for hematuria, and have largely supplanted microscopic urinalysis for screening in asymptomatic patients. Depending on the reference standard used (>2 or >5 RBCs per high-powered field on microscopy), dipstick urinalysis has a sensitivity of 91-100% and a specificity of 65-99% for detecting microscopic hematuria. ^9-16 Dipsticks facilitate testing of serial urine specimens at home, which increases the detection of intermittent hematuria. False-positive dipstick results may be produced by myoglobin in the urine, and false-negative results may result from high concentrations of ascorbic acid, or from prolonged exposure of dipsticks to air. ⁸

Although dipsticks are reasonably accurate for detecting hematuria, microscopic hematuria is not specific for bladder cancer or other urologic cancers. Of the various other causes of microscopic hematuria in asymptomatic patients, most are either benign (e.g., benign prostatic hypertrophy (BPH), exercise, renal cysts, urethral trauma, menstrual bleeding) or of questionable importance (bladder stones, dysplasia, asymptomatic infection). In three separate studies, 46-55% of men with asymptomatic hematuria had no identifiable source of bleeding. ^17-19

Two large outpatient studies have used urine dipsticks to screen for hematuria in asymptomatic populations at increased risk of bladder cancer. In a study by Messing, older men (mean age 65) screened their urine daily for 14 days. Of 1,340 men completing screening, 21% had at least one positive screen and 16 (1.2%) had urologic cancers (9 bladder, 1 renal, and 6 prostate). ¹⁸ Britton recruited 3,152 male outpatients over 60 years old to test their urine 10 times (daily or weekly). At least one screen was positive in 20% of men (12% on initial screen), and 22 (0.5%) had cancer (17 bladder and 5 prostate). ¹⁹ Among men undergoing full evaluation for hematuria, the positive predictive values (PPV) of serial dipstick screening for malignancy in these two studies were 8% and 6%, respectively one third of men with hematuria refused or had an incomplete workup in each study. Similar results have been reported in other populations: among 272 Japanese men with 5 or more RBCs on urinalysis, 6% had urologic cancers. ¹⁷ Hematuria has a higher PPV (26-33%) if other urologic disorders are included as useful outcomes of screening, ^18,20 but the benefit of early detection of many of these conditions (bladder stones, mild obstruction, urinary tract infection) remains unproven in asymptomatic individuals (also see Chapter 31).

The yield of onetime screening for bladder cancer in the general outpatient population appears to be much lower. In a retrospective review of over 20,000 men over 35 and women over 55 receiving a personal health appraisal, dipstick screening detected only three cases of cancer (one bladder, two prostate). ²¹ Prevalence of positive dipstick results ranged from 3-9% over a 7-year period. In a second study of almost 2,700 outpatients, 13% of screened men and women had hematuria (at least one RBC on urine sediment), but only 2% of those with microscopic hematuria had serious urologic disease. ^22,23 In each of these studies, only 0.5% of all patients (3-4% of men over age 55) with asymptomatic hematuria were diagnosed with urologic cancers within 3 years of a positive screen.

Urine cytology is more specific but less sensitive than microscopic hematuria as a screen for early bladder cancer. Because cytology is technically difficult and significantly more expensive than dipstick urinalysis, its use as an initial screening test has been limited to high-risk occupational screening programs. Specificity for cytology has been estimated to be as high as 95%, ²⁴ and sequential screening combining urine dipstick and urine cytology may be able to reduce the false-positive rate of screening while maintaining sensitivity for clinically important cancers. Among men with dipstick hematuria in one screening study, urine cytology detected 10 of 17 patients with bladder cancer with a specificity of 96% 6 of the 7 cases missed were well-differentiated, superficial lesions with a good prognosis. ¹⁹ Rapid tests based on other tumor markers are under investigation. ²⁵

Survival in patients with bladder cancer is strongly associated with stage at diagnosis. Although most cancers are superficial at time of diagnosis, currently 10-20% of all cases of bladder cancer have invaded the muscular wall of the bladder when first diagnosed, with a much worse prognosis. Five-year survival for patients with superficial disease is over 90%, but falls to less than 50% with invasive disease. ¹ The rationale for screening is that detecting and treating early asymptomatic bladder cancers may prevent progression to invasive disease, or allow for more effective treatment of noninvasive tumors, which have a high rate of recurrence. Many cases detected on screening, however, are low-grade transitional cell cancers with low propensity for invasion in contrast, since aggressive cancers may invade early, periodic screening may have a limited potential for detecting lethal bladder cancers at an early, treatable stage. ²⁶

In the prospective screening studies cited above, all 26 cases of bladder cancer detected by screening were early tumors confined to superficial areas of the bladder (Stage T0 or T1). ^18,19 Compared to outcomes of cancers developing in the general population, cases detected by screening appeared to be less likely to progress over 3 years ²⁷ or lead to death within 2 years. ²⁸ Because of lead-time and length biases (see Chapter ii, Methodology), however, comparing case-survival is not sufficient to establish a benefit of screening, without information on rates of cancer and death in a comparable unscreened population. The incidence of invasive and fatal bladder cancer among screened men is very low, and it is also quite low in the general population of older men (<1/1,000 per year). Larger studies, with a comparable unscreened group and longer follow-up, are needed to determine whether screening improves the outcome of bladder cancer in high-risk populations. Despite early detection and treatment, 10 of 16 cancers detected by screening recurred within 3 years in one study. ²⁷

No major organization recommends screening for bladder cancer in asymptomatic adults. The Canadian Task Force on the Periodic Health Examination recommends against routine screening in asymptomatic individuals and concludes that there is insufficient evidence for or against screening in specific high risk groups. ²⁹ The American Cancer Society has not issued any specific guidelines on screening for bladder cancer.

Dipstick and microscopic urinalysis are simple and sensitive tests for detecting hematuria from early tumors, but they are not sufficiently specific to be practical for screening for bladder cancer in the general population. Even among older high-risk populations, the predictive value of a positive screening test is low (5-8%). As a result, many persons without cancer will require diagnostic workups for false-positive test results and will be subjected to the costs, discomforts, and risks of cystoscopy and intravenous pyelography. More important, there is no proof that early detection significantly improves the prognosis for the small minority of patients found to have urologic malignancies. Most of the bladder cancers detected have a good prognosis in the absence of screening: 5-year survival for all bladder cancer is currently close to 80%. ¹ Due to the frequent multifocal nature of bladder cancer, recurrences are common despite early detection and treatment. Conversely, the most lethal tumors become invasive early in the course of disease, and the potential to detect them at an earlier stage may be limited. Only a prospective study that includes an unscreened comparison group can determine whether screening is effective in reducing morbidity or mortality from bladder cancer (or other urologic cancers), and whether the benefits are sufficient to justify the costs and risks of screening and early treatment. In the absence of such evidence, routine screening cannot be recommended, due to the high rate of false-positive results, and the possibility of harm to asymptomatic patients, few of whom have cancer. Primary prevention may offer a safer and more effective strategy than screening for reducing mortality from urologic cancer, since smoking accounts for nearly half of all deaths from cancers of the bladder and kidney. ²

CLINICAL INTERVENTION

Routine screening for bladder cancer with microscopic urinalysis, urine dipstick, or urine cytology is not recommended in asymptomatic persons ("D" recommendation). Persons working in high-risk professions (e.g., dye or rubber industries) may be eligible for screening at the worksite, although the benefit of this has not been determined. Men and women who smoke cigarettes should be advised that smoking significantly increases the risk for bladder cancer, and all smokers should be routinely counseled to quit smoking (see Chapter 54).

The draft update for this chapter was prepared for the U.S. Preventive Services Task Force by David Atkins, MD, MPH, with contributions from materials prepared by Sarvesh Logsetty, MD, for the Canadian Task Force on the Periodic Health Examination.

Thyroid cancer accounts for an estimated 14,000 new cancer cases and more than 1,000 deaths in the U.S. each year. ¹ The annual incidence is about 4/100,000 population. ² Women account for 77% of new cases and 61% of deaths. ¹ Current overall 5-year survival with treatment is 95% in whites and 90% in blacks, ¹ but is much lower with some histologic types (e.g., medullary, anaplastic). ^3-5 Among those at substantially increased risk for thyroid cancer are persons exposed to external upper body (especially head and neck) irradiation during infancy or childhood, and individuals with a family history of thyroid cancer or multiple endocrine neoplasia type 2 (MEN 2) syndrome. ^6-10 The risk of radiation-induced thyroid nodularity and cancer increases with radiation dose and decreases with increasing age at which irradiation occurred. ^7-12 In several large cohort studies, the absolute excess risk of thyroid cancer associated with low-dose irradiation given before 18 years of age ranged from 0.3 to 12.5/10,000 person-years per Gy (Gy = radiation dose). ^8-10 Medullary thyroid cancer, which comprises about 10% of all thyroid malignancies, is inherited in one fourth of cases as part of the autosomal dominant MEN 2 syndrome. ^6,13

Common screening tests for thyroid cancer include neck palpation and ultrasonography to detect nodules. Screening for medullary thyroid cancer as part of the autosomal dominant syndrome MEN 2 is performed at specialized centers ^13a rather than by primary care providers and will not be considered further in this chapter. Diagnostic procedures such as scintigraphy and fine-needle aspiration with cytology are generally reserved for persons with evidence of nodular disease or goiter.

The accuracy of neck palpation as a screening test varies with the examiner's technical skill and the size of the mass. ¹⁴ Among asymptomatic persons, palpation had a reported sensitivity of 38% for any thyroid disease (compared to examination at surgery for hyperparathyroidism), and 4 of 6 thyroid tumors were missed by palpation. ¹⁵ Compared to ultrasonographic examination, the sensitivity of neck palpation for detection of solitary thyroid nodules was only 15%, although no nodules were malignant. ¹⁶ Of 821 patients with no history of thyroid abnormalities and without clinically palpable nodules at autopsy, 100 had solitary nodules on macroscopic inspection of serially sectioned glands, and 17 had primary thyroid cancer. ¹⁷ Direct palpation of the excised thyroid gland at autopsy had a sensitivity for solitary nodules of only 24% compared to macroscopic inspection. These studies suggest a negative examination does not appreciably decrease the probability of thyroid nodules or cancer.

Neck palpation for thyroid nodularity has a high specificity in asymptomatic persons (93-100%), but routine palpation for thyroid nodules as a screening test to detect thyroid cancer generates many false-positive results because only a small proportion of nodular thyroid glands are neoplastic. ^14,17,18 Periodic screening by palpation of almost 77,000 Japanese women detected thyroid cancer in 0.14% the likelihood of thyroid cancer in the presence of a palpable thyroid abnormality was 6%. ¹⁸ A similarly high false-positive rate has been reported when ultrasonography is used as a screening test for thyroid abnormalities. In Finnish studies, ultrasound screening of 354 asymptomatic persons detected 56 solitary nodules, but none was malignant on biopsy. ^16,19 Those falsely identified as positive by screening tests must undergo the inconvenience, expense, and anxiety of needless additional testing, including invasive tests such as biopsy, to rule out cancer.

Persons exposed to upper body irradiation in childhood have a higher prevalence of thyroid cancer, but also have a higher prevalence of thyroid nodularity. ^8-11 It is unclear what effect a history of irradiation has on the likelihood of thyroid cancer in the presence of palpable thyroid nodularity. Periodic screening by neck palpation of 1,500 patients with a history of thyroid irradiation detected carcinoma in 1%. ²⁰ The likelihood of thyroid cancer given detection of any nodular disease was only 3%, but the likelihood of malignancy among patients with nodular disease that was suspicious for cancer (e.g., solitary nodules) was not reported. Only 17% of the patients with nodularity actually underwent surgery, of whom 20% had thyroid cancer.

The benefits of early detection of thyroid cancer in the general population are not well defined. For all histologic types, 5-year survival is significantly better with earlier stage at diagnosis. ³ A cohort study of mass screening found a significantly higher 7-year cumulative survival rate in patients whose cancer was detected by screening (98%) when compared with those presenting with symptoms (90%). ¹⁸ Cancers detected by screening were significantly more likely to have a favorable histology, however, and both lead-time and length biases are likely in this study. There have been no controlled trials demonstrating that asymptomatic persons detected by screening have a better outcome than those who present with clinical symptoms or signs. In addition, not all cancers detected through screening are likely to present clinically during the patient's lifetime. In autopsy studies in the U.S., the prevalence of occult thyroid carcinoma in adults ranges from 2-13% ^17,21,22 in contrast, the annual incidence of thyroid carcinoma is only about 4/100,000 population. ²

The American Cancer Society recommends screening for thyroid cancer by palpation every 3 years in persons aged 21-40 years and annually in those more than 40 years old. ²³ The American Academy of Family Physicians recommends palpation for thyroid nodules in adults with a history of upper body irradiation ²⁴ this recommendation is currently under review. The Canadian Task Force on the Periodic Health Examination concluded that there was poor evidence for either inclusion or exclusion of screening for thyroid cancer in the periodic health examination. ²⁵

Given the lack of evidence that early detection of thyroid cancer by screening improves outcome, the high prevalence and uncertain clinical significance of occult throid carcinoma, the poor sensitivity of neck palpation in the detection of thyroid nodules, the fact that most positive screening tests would be false-positives, and the invasive nature of diagnostic tests (e.g., biopsy) likely to follow a positive screening test, routine screening for thyroid cancer cannot be recommended at this time. For persons irradiated in childhood, the greater likelihood of having both thyroid nodules and malignancy means that the yield from screening is likely to be higher. The clinical benefits of such screening have not been established, however.

CLINICAL INTERVENTION

Screening asymptomatic adults or children for thyroid cancer using either neck palpation or ultrasonography is not recommended ("D" recommendation). Although there is insufficient evidence to recommend for or against such screening in asymptomatic persons with a history of external upper body (primarily head and neck) irradiation in infancy or childhood, recommendations for periodic palpation of the thyroid gland in such persons may be made on other grounds, including patient preference or anxiety regarding their increased risk of cancer ("C" recommendation).

The draft update of this chapter was prepared for the U.S. Preventive Services Task Force by Carolyn DiGuiseppi, MD, MPH.

Approximately 14 million persons in the U.S. have diabetes mellitus. ¹ Non-insulindependent diabetes mellitus (NIDDM) or Type II diabetes accounts for 90-95% of all cases of diabetes in the U.S., while insulin-dependent diabetes mellitus (IDDM) or Type I diabetes accounts for the remaining 5-10%. ^1-4 An estimated half of all persons with diabetes (primarily patients with NIDDM) are currently unaware of their diagnosis. ² Diabetes may cause life-threatening metabolic complications, and is the seventh leading cause of death in the U.S., contributing to roughly 160,000 deaths each year. ^1,3 It is also an important risk factor for other leading causes of death such as coronary heart disease and cerebrovascular disease. ⁴ Diabetes is the most common cause of polyneuropathy, with approximately 50% of diabetics affected within 25 years of diagnosis, ⁵ and is responsible for over 50% of the 120,000 annual nontraumatic amputations in the U.S. ⁶ Diabetic nephropathy is now the leading cause of end-stage renal disease in the U.S. ⁷ and, if current trends continue, will soon account for 50% of all patients with renal failure. ⁸ Diabetes is the leading cause of blindness in adults ages 20-74 and accounts for over 8,000 new cases of blindness each year. ⁹ Infants born of diabetic women are at increased risk of fetal malformation, prematurity, spontaneous abortion, macrosomia, and metabolic derangements. ^10,11 Compared to persons without diabetes, diabetic patients have a higher hospitalization rate, longer hospital stays, and increased ambulatory care visits. ^3,12 The total annual economic burden of diabetes is believed to approach $100 billion in the U.S. ¹³

The onset of NIDDM is usually after age 30, and the prevalence steadily increases with advancing age. It is estimated that nearly 20% of the U.S. population aged 65-74 has diabetes. ² The prevalence of NIDDM is markedly increased in Native Americans and is also higher among black and Hispanic populations. ³ The prevalence of NIDDM is greater than 70% in Pima Indians 55 years of age and older. ¹⁴ Other risk factors for diabetes include family history, obesity, and a previous history of gestational diabetes or impaired glucose tolerance. IDDM has an earlier onset (usually before age 30), a much shorter asymptomatic period, and a more severe clini cal course than NIDDM.

Gestational diabetes mellitus (GDM), the development of glucose intolerance during pregnancy, occurs in 3-5% of all pregnancies and is the most common medical problem of pregnancy. ^3,15 Risk factors for GDM include obesity, increased maternal age, hypertension, glucosuria, a family history of diabetes, and a history of a macrosomic, stillborn, or congenitally malformed infant. GDM is a risk factor for fetal macrosomia and is associated with other neonatal complications, such as hyperbilirubinemia and hypoglycemia. Macrosomia -- most commonly defined as birth weight above 4,000 or 4,500 g -- is not itself a morbid condition but is associated with increased risk of operative delivery (cesarean section or vacuum or forceps delivery) and birth trauma (e.g., clavicular fracture, shoulder dystocia, and peripheral nerve injury). ^16-19 In some series, the incidence of shoulder dystocia in infants over 4,000 g is close to 2%. ²⁰ Women with a history of GDM are also at increased risk for developing NIDDM later in life. ²¹

The diagnosis of diabetes in many nonpregnant patients is based on typical symptoms (polyuria, polydypsia) in association with clear elevation of glucose (fasting plasma glucose > 140 mg/dL [7.8 mM]). Many asymptomatic persons, however, may have abnormal glucose metabolism and be at increased risk for complications of diabetes.

The National Diabetes Data Group (NDDG) ²² and World Health Organization (WHO) ²³ have issued similar criteria for diagnosing diabetes in asymptomatic persons, based on elevated fasting plasma glucose (>140 mg/dL) or an abnormal plasma or serum glucose following an 75 g oral glucose tolerance test (OGTT). NDDG criteria for a positive OGTT (> 200 mg/dL at 2 hours and before 2 hours) differ slightly from WHO criteria (glucose > 200 mg/dL at 2 hours alone). Abnormal glucose measurements on more than one occasion are required for a diagnosis of diabetes. ^22,23 The complex diagnostic criteria reflect both the difficulty in distinguishing diabetic from nondiabetic patients on the basis of a single measurement, and the substantial test-retest variability of the OGTT. The coefficient of variation for OGTT ranges from 20% to 35%. ^24,25 To improve reliability of the OGTT in nonpregnant adults, the American Diabetes Association (ADA) recommends that patients eat an unrestricted diet for 3 days preceding the test and fast overnight before the test. ²⁶

Both the NDDG and WHO recognize an intermediate form of disordered glucose metabolism, impaired glucose tolerance (IGT), based on intermediate results of the OGTT (140-200 mg/dL). ^22,23 Patients with IGT are at increased risk of developing frank diabetes, but rates of progression are highly variable. IGT is also a risk factor for cardiovascular disease. ²⁵ A significant number of individuals diagnosed with IGT revert to normal on repeat testing, ²⁵ and the treatment implications of IGT alone are uncertain.

The diagnosis of GDM is traditionally based on two or more abnormal values during a 3-hour glucose tolerance test using 100 g glucose. ^22,27 NDDG diagnostic criteria are based on extrapolations from standards for whole blood glucose originally derived by O'Sullivan ²⁸ to identify mothers at risk of developing diabetes in long-term follow-up. The conversion factor used to develop criteria for plasma glucose measurements may have been incorrect, however, ²⁹ and others have proposed modified criteria with lower thresholds as more sensitive predictors of adverse pregnancy outcomes. ³⁰ Outside of North America, the diagnosis of GDM is usually based on WHO criteria using a 2-hour 75 g glucose tolerance test. ²³ The prevalence of GDM varies considerably depending on whether WHO, NDDG, or modified criteria of Carpenter and Coustan ³⁰ are used. ^15,31 In addition to poorly standardized criteria for a positive OGTT in pregnancy, the lack of studies on the reproducibility of the 100 g glucose tolerance test contributes to ongoing controversy over the diagnosis of GDM. ^32-34

Because diagnostic glucose tolerance testing is too time-consuming and expensive for routine screening, various blood or urine tests have been examined for their ability to identify three distinct at-risk populations among asymptomatic persons: persons with undiagnosed NIDDM, pregnant women with GDM, and individuals at high risk of developing IDDM.

The most commonly used screening tests for NIDDM include measurement of serum or plasma glucose in fasting or postprandial specimens, measurement of glycosylated proteins in blood, and detection of glucose in urine. The sensitivity and specificity of the fasting plasma glucose (compared to diagnostic oral glucose tolerance testing) depends on the threshold set to define an abnormal screening result. A single fasting glucose above 140 mg/dL is specific for diabetes (>99%) but sensitivity varies widely among different populations (21-75%). ^35-40 Using a lower threshold (>123 mg/dL) improves sensitivity (40-88%), while maintaining reasonably high specificity (97-99%). ^35-40 A random (i.e., nonfasting) plasma glucose greater than 140 mg/dL has a sensitivity of 45% and a specificity of 86%. ⁴¹ The ADA recommends that a fasting plasma glucose greater than 115 mg/dL, or a random glucose greater than 160 mg/dL, be considered a positive screen to be confirmed with OGTT. ²⁶

The nonenzymatic attachment of glucose to circulating proteins, primarily hemoglobin and albumin, reflects overall metabolic control in diabetic populations. A number of studies have evaluated HbA1c and serum fructosamine as screening tests for diabetes. ^40,42-45 Test characteristics are more variable than fasting plasma glucose, with sensitivity ranging from 15% to 93% and specificity from 84% to 99%.

Presence of glucose in the urine is fairly specific but less sensitive than most blood tests for NIDDM. In population-based screening using semiquantitative urine dipstick, a "trace positive" dipstick result or greater has a reported sensitivity of 23-64% and specificity of 98-99%. ^40,46 In a high-risk population, quantitative assays of urine glucose achieved high sensitivity (81%) with high specificity (98%), comparable to both fasting plasma glucose and glycosylated protein assays. ⁴⁰

Sensitivity of all screening tests increases with the severity of hyperglycemia among the diabetic population. ⁴⁰ Both the sensitivity and positive predictive value of screening tests will be highest in high-risk populations such as Native Americans and African Americans, where undiagnosed diabetes and severe hyperglycemia are more prevalent. ⁴⁰ In the asymptomatic general population, where the prevalence of undiagnosed diabetes is only 1-3%, a greater proportion of diabetic patients may be missed by screening, and many persons with a positive screening test will not have diabetes. Screening asymptomatic persons may have some harmful effects, including an increase in false-positive diagnoses in a review of 112 patients being treated for diabetes in a general practice, nine (8%) patients, all without classic symptoms, were found not to have diabetes on further evaluation. ⁴⁷ Even a true-positive diagnosis could have adverse consequences for an asymptomatic person if it causes "labeling" effects ⁴⁸ or difficulty obtaining insurance.

The Third International Workshop Conference on Gestational Diabetes has recommended screening pregnant women at 24-28 weeks of gestation with a 50 g 1-hour oral glucose challenge test, performed in fasting or nonfasting state. ²⁷ Patients with plasma glucose of 140 mg/dL (7.8 mM) or greater at 1 hour should undergo a diagnostic 3-hour OGTT. There is no single threshold that accurately separates normal from abnormal results on the glucose challenge test, however. ²⁷ Estimates of sensitivity of screening under this protocol range from 71% to 83% with a specificity of 78%-87%. ^30,49,50 Sensitivity is increased by using a lower threshold for a positive screen ^30,51 and by testing in the fasting state. ⁴⁹ A large prospective study of nearly 4,300 pregnant women reported that using higher cutpoints (142-149 mg/dL) and adjusting for time since last meal could reduce the misclassification of patients based on initial screening tests. ⁵² Reproducibility of the 1 hour glucose challenge test is only fair, ⁵³ but it improves with advancing gestational age. ⁵⁴ In an unselected pregnant population (prevalence of GDM approximately 3%), fewer than one in five women with a positive glucose challenge test will meet criteria for gestational diabetes on a full OGTT. ⁵²

The elevations in plasma glucose in GDM are less pronounced than in IDDM or NIDDM. As a result, neither serum glycosylated proteins ^51,55-58 nor urine glucose ³⁴ are sufficiently sensitive for detecting GDM. In addition, glucosuria is common among nondiabetic pregnant women. Random blood glucose has been advocated as a simpler and less costly screening test for GDM ^59,60 but its test performance has not been fully evaluated. A large prospective study is comparing fasting and random plasma glucose to oral glucose challenge for detecting GDM and for predicting adverse perinatal outcomes. ⁵²

A growing body of evidence indicates that IDDM is a genetically linked autoimmune disorder, in which progressive destruction of insulin-producing pancreatic islet cells eventually leads to complete dependence on exogenous insulin. ⁶¹ Islet cell autoantibodies and insulin autoantibodies are pres- ent in the majority of patients with newly diagnosed IDDM, ⁶² and may precede the onset of clinical symptoms by months to years. Immunoassays for islet cell antibodies remain difficult to standardize, ⁶³ however, and appear to be of limited value for screening in the general population. In individuals without a family history of IDDM, the prevalence of islet cell autoantibodies ranges from 0.3% to 4.0% and the chance of developing IDDM in antibody-positive individuals is estimated to be less than 10%. ⁶⁴ The potential value of immune markers is greater in high-risk individuals (i.e., first-degree relatives of affected patients). Several studies report that a combination of immune markers and measures of insulin responsiveness can identify a population at very high risk (up to 70%) of developing IDDM. ^62,63,65 This high risk may make such persons appropriate candidates for experimental interventions to reduce the risk of progression to IDDM. Only 10% of all cases of IDDM, however, occur in persons with a positive family history.

Up to 20% of patients with newly diagnosed NIDDM already have early retinopathy, suggesting that the onset of diabetes may be many years (estimated 9-12 years) before clinical diagnosis, and that the microvascular changes may precede overt symptoms in many patients. ⁶⁶ Earlier detection through screening might provide an opportunity to reduce the progression of microvascular or macrovascular disease due to asymptomatic hyperglycemia. Animal models of diabetes suggest that hyperglycemia is the underlying cause of microvascular complications, ⁶⁷ and numerous epidemiologic studies confirm that the degree of hyperglycemia and duration of disease are associated with microvascular complications such as nephropathy, retinopathy, and neuropathy. ^5,68-72 Direct evidence that improving glucose control reduces the incidence of these complications has only recently become available, and only for patients with IDDM. In the Diabetes Control and Complications Trial (DCCT), over 1,400 subjects with IDDM were randomized to intensive insulin therapy versus conventional treatment. Intensive insulin therapy improved average blood glucose, significantly reduced progression of existing retinopathy, and significantly lowered the incidence of retinopathy, neuropathy, and nephropathy in all patients. ^73,74

The DCCT study is generally regarded as providing strong evidence of the role of hyperglycemia in diabetic microvascular disease, but questions remain about extrapolating its results to the management of patients with NIDDM. ⁷⁵ The incidence of microvascular complications is lower in NIDDM than IDDM, and the largest controlled trial to date of treatment of NIDDM (the University Group Diabetes Program study) found no effect of improved glucose control with insulin or drug thera py on retinopathy. ⁷⁶ More definitive results may come from the U.K. Prospective Diabetes Study (UKPDS), which randomized 2,520 patients with newly diagnosed NIDDM controlled with diet to diet alone, or additional therapy with chlorpropamide, glibenclamide, metformin, or insulin. ⁷⁷ Three-year results indicated that patients receiving drug or insulin therapy had significantly better glucose control but greater weight gain and more frequent episodes of hypoglycemia. ⁷⁸ Data on other clinical outcomes are not yet available.

Patients with diabetes are at significantly increased risk for coronary heart disease, stroke, and peripheral vascular disease cardiovascular diseases combined account for the majority of deaths in diabetic patients. The risk of cardiovascular disease, however, is not clearly associated with either disease duration or degree of glycemic control. The rate of increase in coronary heart disease risk over time is similar in patients with NIDDM and in nondiabetic patients. ^79,80 In 8-year follow-up of almost 500 diabetic men and women, disease duration was associated with risk of ischemic heart disease in patients with IDDM but not in those with NIDDM, ⁸¹ and there was no correlation between cerebrovascular and peripheral vascular events and diabetes duration. Detecting such an association may be complicated by difficulty in accurately ascertaining the onset of diabetes in patients with NIDDM. Insulin resistance and hyperinsulinemia may be more important determinants of macrovascular complications than degree of glucose control. ^79,82 In the UGDP study, neither cardiovascular disease nor mortality was reduced by improved glucose control in the intervention groups, ⁷⁶ but the interpretation of these findings has been criticized. ⁸³ Drug therapy for NIDDM carries the risk of hypoglycemia. In the UKPDS study, the annual incidence of hypoglycemia was 28% for patients on glibenclamide, and 33% for those on insulin episodes requiring medical therapy occurred in 1.4% of subjects each year. ⁷⁸

The majority of individuals in the U.S. who have disordered glucose metabolism have IGT. ⁸⁴ Untreated, most persons with IGT do not develop diabetes, but the reported cumulative incidence of diabetes at 10 years has varied from 15% to 61%. ²⁵ Progression to diabetes is highest in some Native American populations. ⁸⁵ There is little direct evidence of a benefit of detecting and treating IGT. ^86,87 Prospective studies of interventions to prevent progression to frank diabetes in patients with IGT have produced conflicting results. One trial of dietary and pharmacologic treatment ⁸⁸ and a nonrandomized trial of diet and physical activity training ⁸⁹ each reported a reduced incidence of diabetes, whereas other prospective studies have reported no effect on the rate of progression to diabetes. ^90-92

GDM is associated with increased risk of fetal macrosomia, birth trauma, neonatal hypoglycemia, and perinatal mortality. ^93-96 No properly controlled trial has examined the benefit of universal or selective screening compared to routine care without screening. In two retrospective analyses, no significant difference in macrosomia or in birth trauma was found in women screened for GDM compared to unscreened control populations. ^97,98 Because women screened for GDM are more likely to be at high risk, such studies cannot reliably exclude a benefit of screening. ⁹⁸

The clearest benefit of screening is the potential for treatment to reduce the incidence of fetal macrosomia in women with GDM. Although modified diet can reduce hyperglycemia in GDM, only one controlled trial has examined the effect of dietary therapy on clinical outcomes in GDM. ⁹⁹ A total of 158 women with mild GDM (positive by NDDG criteria but not WHO criteria) were randomized to diet treatment or no therapy there were no significant differences in perinatal outcomes, although slightly fewer infants over 4,000 g were born to diet-treated mothers (3 vs. 5). ¹⁰⁰ Several randomized controlled trials have demonstrated that diet and insulin (compared to diet alone) results in improved glucose control and reduced incidence of macrosomia in women with GDM. ^94,101,102 Macrosomia was not significantly reduced in a fourth trial, but 15% of the women assigned to diet therapy received insulin because glucose control was inadequate. ¹⁰³ An overview of four randomized trials estimated that treatment of GDM with diet and insulin, compared to diet alone, reduced the incidence of macrosomia by two thirds (6% vs. 17%). ¹⁰⁴ Despite a reduction in macrosomia, there were no significant differences in rates of cesarean section, forceps delivery, or birth trauma between treated and control groups in any of the prospective trials, however. There was only one reported instance of shoulder dystocia among 140 births in the two trials reporting this outcome. ^101,104 In a retrospective analysis of 445 gestational diabetics, women who received both insulin and dietary treatment had significantly lower rates of birth trauma and operative delivery than women who received dietary treatment alone or no intervention. ⁹⁶ Since treatment was not randomly assigned, factors other than treatment may have contributed to the differences in outcomes.

The benefit of improved glucose control on other outcomes in GDM, including perinatal mortality, remains uncertain. Although several case series have reported marked improvements in perinatal death rates with treatment of GDM, ^{95,97,105-107} none of these studies employed an appropriate control group. The use of historical controls (i.e., outcomes of prior pregnancies) or general population controls is likely to exaggerate the apparent benefits of treatment. In an overview of five randomized trials, there was no significant difference in perinatal mortality among women treated with diet and insulin (2.7%) and those treated with diet alone (3.2%). ¹⁰⁴ Moreover, in trials conducted after 1975, there were no perinatal deaths in treated or control groups. ^100,104 In one trial, insulin treatment was associated with lower rates of neonatal jaundice and nonsignificant reductions in admissions to the neonatal ICU. ¹⁰⁸ At the same time, treatment of GDM may have adverse effects for some women. In one retrospective analysis, women with GDM who maintained tight glucose control (mean glucose < 87 mg/dL) had a higher incidence of small-for-gestational age infants than nondiabetic controls. ¹⁰⁹

Degrees of hyperglycemia more subtle than in GDM may result in increased maternal and neonatal complication rates. ^110-112 The incidence of macrosomia and preeclampsia/eclampsia is higher in women who demonstrate at least one abnormal result among the four points on a glucose tolerance test. The prevalence of mildly hyperglycemic pregnant women who do not meet the criteria for GDM but are at increased risk during pregnancy is unknown.

Although treatment of GDM can reduce macrosomia, the impact of widespread screening and treatment on the overall incidence of macrosomia and dystocia may be quite small. The reported incidence of macrosomia in the general population varies from 1% to 8%, ^93,113 and most macrosomic infants are born to women without GDM. ¹¹⁴ Gestational diabetes was responsible for only 5% of infants over 4,500 g in one study, ¹¹⁵ and it is estimated to account for only 5% of shoulder dystocia cases in this country. ¹¹⁶ Other factors such as maternal obesity, gestational weight gain, and maternal age may be more important determinants of macrosomia and adverse outcomes. ¹¹⁷ In a prospective study of GDM controlled with diet, the only significant predictor of birth weight was maternal weight at delivery plasma glucose levels were poor predictors of birth weight. ¹¹⁸

Earlier diagnosis of IDDM could be of considerable benefit if treatment could arrest the disease process before severe insulinopenia and hyperglycemia had developed. A number of recent trials have examined whether immunosuppressive agents can delay disease progression in patients with new-onset IDDM. ⁶¹ Although some patients have experienced prolonged remissions, the benefit has not been sustained in most patients, and the serious adverse effects of immunosuppressive agents are likely to preclude their use in completely asymptomatic persons. There have been several promising small trials of other interventions to prevent IDDM in high-risk asymptomatic persons, enrolling individuals identified by autoantibodies levels and other physiologic measures. ^63,119,120 Multicenter randomized clinical trials are currently underway to determine whether prophylactic regimens of insulin or nicotinamide can prevent progression to IDDM in such high-risk subjects. ⁶¹

The Canadian Task Force on the Periodic Health Examination (CTF), ¹²¹ the American College of Physicians (ACP), ¹²² and the American Academy of Family Physicians ¹²³ recommend against routine screening for diabetes among asymptomatic nonpregnant adults each of these organizations concluded that selective screening may be reasonable among individuals at high risk of developing diabetes (e.g., older obese persons, th ose with a strong family history). AAFP policy is currently under review. The ADA recommends screening all individuals with a careful history and measuring fasting glucose on those with identified risk factors for developing diabetes, including obesity, family history, history of GDM, selected medical conditions, or selected ethnic background. ¹²⁴ A 1994 report of the WHO concluded that population screening for NIDDM was not justified, but that opportunistic screening of high-risk persons may be useful to permit earlier intervention. ¹²⁵

The ACP, ¹²² the ADA, ¹²⁴ and the Third International Workshop Conference on Gestational Diabetes ²⁷ recommend universal screening for GDM in pregnant women between weeks 24 and 28 using a 1-hour glucose tolerance test. The American College of Obstetricians and Gynecologists and the American Academy of Pediatrics do not recommend universal screening in pregnancy but strongly recommend screening pregnant women in certain high-prevalence populations (e.g., Native Americans) and those with specific risk factors (age over 30, family history of diabetes, previous macrosomia, malformed or stillborn infants, hypertension, or glucosuria). ^126,127 The CTF concluded that there was insufficient evidence to recommend for or against universal screening for GDM, but suggested close monitoring of women with risk factors for GDM. ¹²¹

Screening for diabetes in asymptomatic adults suffers from two important limitations: the lack of a practical screening test that is both sensitive and specific, and insufficient evidence that detection of diabetes in the asymptomatic period significan tly improves long-term outcomes. Even if improving glucose control can reduce long-term complications of NIDDM, many other factors must be considered in determining the likely benefits and risks of screening in asymptomatic persons: efficacy of diet or medications in reducing glucose levels compliance of asymptomatic persons with lifestyle advice possible risks of drug or insulin therapy inconvenience and costs of screening, follow-up, and treatment and the potential adverse effects of screening (false-positive diagnoses, "labeling" of asymptomatic persons). Targeting screening to high-risk groups (certain ethnic populations, older overweight subjects) and emphasizing interventions that are inexpensive and safe (exercise, prudent diet, and weight loss) are likely to minimize the potential adverse effects of screening. Since most of these interventions are recommended for all adults, the additional benefit of screening to promote lifestyle interventions remains uncertain. If the ongoing UKPDS trial demonstrates important clinical benefits from more intensive interventions (i.e., drug or insulin therapy) in patients with minimally symptomatic NIDDM, this would provide stronger support for screening for diabetes among asymptomatic adults.

The value of widespread screening for GDM is also unproven. Important questions remain about the diagnostic gold standard, the optimal screening test, and the appropriate management of GDM. Although there is good evidence that insulin treatment can reduce the incidence of macrosomia in GDM, evidence of a benefit on clinically important perinatal outcomes (birth trauma, operative delivery, neonatal metabolic derangements, or perinatal mortality) is much weaker. The high risk associated with GDM in earlier cohorts primarily reflects adverse outcomes in women who were older, overweight, or otherwise at increased risk. Universal screening is likely to have only a small impact on the overall incidence of macrosomia and birth trauma and may subject many low-risk women to the inconvenience, costs and possible risks of follow-up testing, dietary restriction, or insulin management. A 1988 study estimated that universal screening would cost $8,000 per case of macrosomia prevented. ¹²² By one estimate, however, up to 10,000 women would need to be screened to prevent 50 cases of macrosomia, 6 cases of shoulder dystocia, and 1 case of shoulder girdle injury (few of which cause lasting problems). ¹²⁸ Targeting screening to women with risk factors for GDM (including older age), with emphasis on dietary management of GDM, is likely to minimize the adverse effects and costs of screening. Direct evidence of a benefit of screening on important clinical outcomes is not available for any group, however.

Immune markers are not sufficiently specific to recommend their use in the general population at this time. Screening persons with a family history of IDDM using immune markers and physiologic measurements can identify a small number of persons at very high risk of developing IDDM. Patients with a family history account for only 10% of all cases of IDDM, however, and trials of interventions to prevent IDDM in high-risk patients have not yet been completed.

Primary prevention may be a more effective means to reduce diabetes-associated morbidity than widespread screening. Diet, exercise, and weight reduction can safely improve glucose tolerance and are likely to have independent benefits on other important chronic diseases (see Chapters 55 and 56). Whether diabetes screening improves compliance with generally recommended lifestyle interventions has not been determined.

CLINICAL INTERVENTION

There is insufficient evidence to recommend for or against routine screening for NIDDM in nonpregnant adults ("C" recommendation). Although evidence of a benefit of early detection is not available for any group, clinicians may decide to screen selected persons at high risk of NIDDM on other grounds, including the increased predictive value of a positive test in individuals with risk factors and the potential (although unproven) benefits of reducing asymptomatic hyperglycemia through diet and exercise. Individuals at higher risk of diabetes include obese men and women over 40, patients with a strong family history of diabetes, and members of certain ethnic groups (Native Americans, Hispanics, African Americans). In persons without risk factors, screening for asymptomatic disease is much less likely to be of benefit, due to the low burden of disease and the poor predictive value of screening tests in low-risk persons. Measurement of fasting plasma glucose is recommended by experts as the screening test of choice the frequency of screening is left to clinical discretion.

There is also insufficient evidence to recommend for or against routine screening for GDM ("C" recommendation). Although a clear benefit of screening on perinatal morbidity has not been demonstrated for any group, clinicians may decide to screen high-risk pregnant women on other grounds, including the higher burden of disease, and the potential clinical benefits from reducing macrosomia due to GDM. Risk factors for GDM include obesity, older maternal age, a family history of diabetes, and a history of macrosomia, fetal malformation, or fetal death. The 1-hour 50 g glucose challenge test, with confirmation of abnormal results with a 3-hour 100 g oral glucose tolerance test, is the screening test recommended by expert panels in the U.S.

Screening with immune markers to identify asymptomatic individuals at risk for developing IDDM is not recommended in the general population ("D" recommendation).

The draft update of this chapter was prepared for the U.S. Preventive Services Task Force by M. Carrington Reid, MD, PhD, Harold C. Sox, Jr., MD, Richard Comi, MD, and David Atkins, MD, MPH.

Hyperthyroidism and hypothyroidism together account for considerable morbidity in the U.S. The total prevalence of these two disorders in adolescents and adults is estimated to be 1-4% prevalence is higher in women and persons with Down syndrome, and increases with increasing age. ^1-10 The annual incidence in adults has been estimated to be 0.05-0.1% for hyperthyroidism and 0.08-0.2% for hypothyroidism, with the higher incidences cited occurring in elderly women. ^2,11 In adolescents, an incidence of 0.06%/year for these two disorders has been reported. ⁵ Symptoms of thyroid dysfunction, involving the nervous, cardiovascular, and gastrointestinal systems, may have an important impact on health and behavior. ¹² Rarely, fatalities may occur due to thyroid storm in hyperthyroidism and myxedema coma in hypothyroidism. ¹³ Thyroid dysfunction during pregnancy is associated with an increased risk of adverse maternal and fetal outcomes. ^14-18 Most patients with thyroid dysfunction will present with typical clinical symptoms and signs within a few months of disease onset, although overt disease may occasionally be overlooked. Studies in which asymptomatic adults of all ages were screened in the clinical setting, often using older, less sensitive tests, detected previously unsuspected thyroid disease in 0.6-0.9% of persons screened. ^2,3,19,20

The clinical diagnosis of thyroid dysfunction can be more difficult in certain high-prevalence populations, including the elderly, those with Down syndrome, and postpartum women, possibly delaying treatment and risking complications. ¹³ Older persons may experience apathetic hyperthyroidism, without the goiter, ophthalmopathy, and signs of sympathetic nervous system hyperactivity typically seen in younger persons. ²¹ Typical symptoms and signs of hypothyroidism, like fatigue, constipation, dry skin, and poor concentration, may be confused with symptoms of aging, ²² and may also occur less frequently in elderly hypothyroid patients. ²³ Screening persons 60 years or older in the clinical setting detects previously unsuspected hyperthyroidism in 0.1-0.9% and hypothyroidism in 0.7-2.1%. ^2,19,24-27 The clinical diagnosis of hypothyroidism may also be overlooked in patients with Down syndrome because some symptoms and signs, such as slow speech, thick tongue, and slow mentation, are typical findings of both conditions. ^6,7 Screening persons with Down syndrome has detected previously unrecognized thyroid disease, primarily hypothyroidism, in 2.9% (range 0-6.5%). ^6,7,28 Screening reveals thyroid dysfunction, primarily thyroiditis, in 4-6% of postpartum women. ^29-32 This dysfunction is sometimes accompanied by nonspecific symptoms, such as fatigue, palpitations, impaired concentration, or depression, ^31,33,34 that may be mistakenly attributed to the postpartum condition. Women with a personal or family history of thyroid or autoimmune disease, or with thyroid antibodies, are at increased risk for postpartum thyroid dysfunction. ^16,30,35-37 Postpartum thyroid dysfunction is usually transient, but it may require short-term treatment to control symptoms.

Subclinical thyroid dysfunction as typically defined in the literature is a biochemical abnormality, ³⁸ characterized by an abnormal level of thyroid-stimulating hormone (TSH) with otherwise normal thyroid tests and no clinical symptoms. Subclinical hypothyroidism, recognized by an elevated TSH level, is seen in 6-8% of adult women and 3% of adult men. ¹ As with overt disease, the prevalence is higher in the elderly and in persons with Down syndrome. ^{6,7,24,25,27,28,39-41} Progression to overt hypothyroidism occurred in <= 2% of patients who had subclinical hypothyroidism without evidence of thyroid autoimmunity or prior thyroid-related disorders and who were followed for 2-15 years in those with thyroid antibodies, however, progression occurs in about 5-7%/year, and in as many as 20-24%/year in elderly patients with antibodies. ^{25,28,39,42-45} Other than the risk of developing overt hypothyroidism, the importance of subclinical hypothyroidism is unknown. Case series have suggested adverse effects of an isolated elevated TSH level on blood lipid profile, myocardial function, and neuropsychiatric function, ^22,46-48 but controlled observational studies have reported conflicting evidence regarding an association between subclinical hypothyroidism and any of these adverse effects. ^49-54

Subclinical hyperthyroidism, recognized by a subnormal TSH level, is seen in 0.2-5% of the elderly population <= 1%/year progress to overt disease. ^11,40,55,56 Subnormal levels of TSH are often transient, returning to normal without intervention. ^3,25,57 There is limited evidence of risk from subclinical hyperthyroidism except when it is due to excessive thyroxine replacement. Case series have reported subclinical hyperthyroidism in a number of patients with atrial fibrillation. ^58-61 Older controlled observational studies found no association between subclinical hyperthyroidism and atrial fibrillation, ^62,63 but a significant association was reported in one carefully controlled cohort study that used a sensitive TSH assay. ⁵⁷ One controlled study reported a significantly lower total cholesterol level in patients with a subnormal TSH level, ⁵¹ suggesting a possible benefit of this condition.

Thyroid function tests to detect thyroid disease, including total thyroxine (TT₄), free thyroxine (FT₄), and TSH, are influenced by a variety of diagnostic and biologic factors that may affect their accuracy. For example, while TT₄ is usually elevated in hyperthyroidism, it misses 5% of cases that are due to triiodothyronine (T₃) toxicosis. ⁶⁴ TT₄ concentration is strongly influenced by the concentrations and binding affinities of thyroxine-binding globulin and other thyroid-binding proteins. ³⁸ Falsely abnormal TT₄ results often occur with conditions that affect these proteins, such as pregnancy, use of certain drugs, and nonthyroidal illness. ^38,64 FT₄ has the advantage over TT₄ of being independent of thyroid-binding protein concentrations. Equilibrium dialysis (ED), regarded as the reference method for FT₄, is not suitable for routine screening due to its high cost. ^38,65 Immunoassay or index (FTI) methods to estimate FT₄ are simpler, less expensive than ED, and have specificities of 93-99% compared to ED ^20,66-68 these methods are not always independent of thyroid-binding protein concentrations, however, ^38,69 and they may show substantial interlaboratory variation. ⁶⁵ TT₄ and FT₄ cannot be reliably measured in ill patients, because a substantial proportion will have abnormal thyroid function in the absence of true thyroid disease, due to "sick euthyroid syndrome." ^69-71 Screening with TT₄ or FT₄ will generate many false-positive results in healthy populations. ^2,19,20,71 With test specificities in the mid-90% range or lower, the low prevalence of previously unsuspected thyroid disease means that the likelihood of disease given an abnormal test will be quite low. In one study, thyroid disease requiring treatment was found in only 13% of those with abnormal FTI results. ²⁰ Because TT₄ and FT₄ are normal by definition in subclinical thyroid dysfunction, they are not useful as screening tests for this condition.

The immunometric ("sensitive") TSH (sTSH) assays detect low as well as high serum TSH levels, and have become the standard for detecting hyperthyroidism and hypothyroidism. They therefore offer promise as first-line thyroid screening tests. In unselected populations, sTSH has a sensitivity of 89-95% and specificity of 90-96% for overt thyroid dysfunction, as compared to reference standards incorporating clinical history, examination, repeat measurement, and/or additional testing including thyrotropin-releasing hormone tests. ^3,40,68 In an asymptomatic older population, the likelihood of thyroid disease given an abnormal sTSH was only 7%, however, reflecting the low prevalence of disease in healthy people. ⁴⁰ Acutely ill patients, pregnant women, and persons using certain drugs such as glucocorticoids may have false-positive sTSH results, ^38,72,73 although specificity is better than for TT₄ and FT₄ when the three tests have been directly compared. ^38,74 Newer sTSH assays reduce but do not eliminate false-positive diagnoses in such patients. ^75-77 sTSH may respond slowly to abrupt changes in thyroid function, ³⁸ such as those that occur after treatment for hyperthyroidism, but such changes are not generally relevant to the screening of asymptomatic patients.

Screening for occult thyroid dysfunction in adults would be valuable if there were clinical benefits of early treatment, including relief of previously unrecognized symptoms. We found no studies evaluating the treatment of hyperthyroidism detected by screening in asymptomatic persons, or of subclinical hyperthyroidism in persons with atrial fibrillation. Uncertainties about the benefits of treating hyperthyroidism detected by screening are particularly important because of the costs and potential adverse effects (e.g., agranulocytosis, induced hypothyroidism, surgical complications) of treatment with antithyroid medications, radioactive iodine ablation, or subtotal thyroidectomy. ^78,79

Several studies have evaluated the effectiveness of treating patients with subclinical hypothyroidism. Most of the subjects had previously identified thyroid disease, however, and the results may not apply to asymptomatic patients identified only by screening. In a randomized placebo-controlled trial of 33 women with subclinical hypothyroidism, all with a past history of treated hyperthyroidism, there were significant improvements in myocardial contractility and in previously unrecognized symptoms, but no significant changes in basal metabolic rate, pulse, body weight, skin texture, or serum lipid levels. ⁸⁰ The long-term clinical importance of subtle changes in myocardial contractility is unknown. An uncontrolled experiment in 17 women identified by screening found a significantly improved mean clinical symptom score after treatment, mixed effects on myocardial function, and no effect on cholesterol, resting heart rate, body mass, or blood pressure. ⁸¹ Methodologic flaws make it difficult to interpret the results of this study. Uncontrolled experiments in adult patients, mostly women, with subclinical hypothyroidism due to previously identified thyroid disease have reported variable improvement in myocardial function but little effect on lipoproteins with thyroxine treatment. ^82-89 A randomized controlled trial measuring the effects of thyroid replacement on quality of life, lipids, neuropsychological function, bone mineral density, and myocardial function in elderly patients with subclinical hypothyroidism is ongoing (personal communication, Dr. R. Jaeshke, St. Joseph's Hospital, Hamilton, Ontario, August 4, 1995).

In children and adults with Down syndrome and subclinical hypothyroidism, a double-blind crossover placebo-controlled trial failed to document any cognitive, social, or physical changes attributable to 8-14 weeks of thyroxine treatment, ⁴¹ although treatment duration may have been inadequate to effect change. There is otherwise little evidence regarding the benefits of early intervention in these individuals.

Thyroxine replacement therapy can have adverse effects with even moderate degrees of overtreatment (as detected by low TSH or high TT₄ levels), including decreased bone density compared to matched controls. ^90-93 Reduced bone density could increase the risk of fractures in the elderly, but one large series found no significant difference in risk for fractures (or for ischemic heart disease) in treated patients with normal TSH levels compared to those with suppressed TSH due to overtreatment. ⁹⁴ The fracture rate in the two groups was the same as in the general population, while the risk of ischemic heart disease was higher in treated patients irrespective of TSH levels. The study was not designed to determine whether the latter finding was due to treatment or to the underlying disease, however. A small randomized controlled trial in postmenopausal women with subclinical hypothyroidism found no bone density reduction after 14 months of appropriate thyroxine treatment. ⁹⁵ Evidence therefore suggests against an adverse impact of appropriate thyroxine treatment.

No organizations recommend routine screening for thyroid disease in the general population, except screening newborns for congenital hypothyroidism (see Chapter 45). The American Academy of Family Physicians (AAFP) ⁹⁶ and the American Association of Clinical Endocrinologists ⁹⁷ recommend measuring thyroid function periodically in all older women. The policy of the AAFP is currently under review. The Canadian Task Force on the Periodic Health Examination recommends maintaining a high index of clinical suspicion for nonspecific symptoms consistent with hypothyroidism when examining perimenopausal and postmenopausal women. ⁹⁸ The American College of Physicians recommends screening women over age 50 with one or more general symptoms that could be caused by thyroid disease. ⁹⁹ The American College of Obstetricians and Gynecologists recommends that physicians and patients be aware of the symptoms and risk factors for postpartum thyroid dysfunction, and evaluate patients when indicated. ¹⁰⁰ The American Academy of Pediatrics recommends that children with Down syndrome have thyroid screening tests at 4-6 and 12 months of age, and annually thereafter. ¹⁰¹ The American Thyroid Association recommends screening thyroid function in elderly patients, postpartum women, and all patients with autoimmune disease or with a strong family history of thyroid disease, using serum TSH measurement. ^64,102

The prevalence of unsuspected thyroid disease in healthy people in the general population is very low. Despite the high specificity of thyroid function tests such as the newer TSH assays, their routine use in the asymptomatic general population results in many false-positive results. Because of the low prevalence of unsuspected disease, only 1 in 5-10 persons with abnormal screening tests will prove to have thyroid disease. Given the low risk, the lack of evidence that treatment of subclinical thyroid disease identified by screening results in important health benefits, and the potential adverse effects of treatment, screening the asymptomatic general population is not recommended.

The prevalence of thyroid disease is higher in certain populations, including elderly persons (particularly women), persons with Down syndrome, and postpartum women, and these patients might be candidates for thyroid function testing if the results could provide an explanation for nonspecific and insidious symptoms, such as fatigue, memory impairment, or depression, that might be attributed mistakenly to other medical or psychiatric causes. Clinicians should therefore maintain a high index of suspicion for such nonspecific symptoms, and for thyroid disease when these types of symptoms are found, when examining high-risk patients. There is, however, little evidence that routinely screening high-risk patients results in important clinical benefits.

CLINICAL INTERVENTION

Routine screening for thyroid disease with thyroid function tests is not recommended for asymptomatic children or adults ("D" recommendation). This recommendation does not mean that clinicians should not monitor thyroid function in patients with a previous history of thyroid disease. There is insufficient evidence to recommend for or against screening for thyroid disease with thyroid function tests in high-risk patients, including elderly persons, postpartum women, and persons with Down syndrome, but recommendations may be made on other grounds, such as the higher prevalence of disease and the increased likelihood that symptoms of thyroid disease will be overlooked in these patients ("C" recommendation). Clinicians should remain alert for subtle or nonspecific symptoms of thyroid dysfunction when examining such patients, and maintain a low threshold for diagnostic evaluation of thyroid function. Examples of such symptoms include easy fatiguability, weight gain, dry skin or hair, cold intolerance, difficulty concentrating, depression, nervousness, and palpitations. If screening is performed, the preferred test is measurement of thyroid-stimulating hormone (TSH) using a sensitive immunometric or similar assay, because of its superior sensitivity and specificity. Screening for congenital hypothyroidism is discussed in Chapter 45.

The draft update of this chapter was prepared for the U.S. Preventive Services Task Force by Carolyn DiGuiseppi, MD, MPH.

Obesity is an excess of body fat. ¹ Most epidemiologic studies rely on indices of relative weight, such as body mass index (BMI), an index of body weight that is normalized for height, to estimate the prevalence of obesity. [a] For example, the National Center for Health Statistics currently uses the 85th percentile sex-specific values of BMI for persons aged 20-29 (>=27.8 kg/m² for men and >=27.3 kg/m² for women) from the second U.S. National Health and Nutrition Examination Survey (NHANES II) as a cutoff to define overweight in adults. ²

Approximately one third of adult Americans aged 20 and older are estimated to be overweight, based on data from NHANES III. ³ Using 1990 census figures, this corresponds to 58 million people. The prevalence of overweight in the United States has increased dramatically during the past 15 years in men and women of all age and ethnic groups, and remains disproportionately high among black and Hispanic women. ³ Other groups that have a high prevalence of obesity include Asian and Pacific Islanders, Native Americans and Alaska Natives, and Native Hawaiians. ⁴ The prevalence of overweight among adolescents has also increased. ⁵ Based on NHANES III data, about one fifth of adolescents aged 12-19 are overweight. ⁵ The prevalence of obesity among younger children is uncertain, but is estimated to be between 5% and 25%, ⁶ and may also be increasing. ⁷

Increased mortality in adults has been clearly documented as a result of morbid obesity, weight that is at least twice the desirable weight. ^8,9 Less severe obesity (e.g., as low as 26.4-28.5 kg/m ² ) has also been associated with increased mortality in large prospective cohort studies. ^10-13 Although some studies have reported greater mortality among the thinnest individuals, ¹⁴ a 1993 prospective cohort study that carefully controlled for smoking and illness-related weight loss found a linear relationship between BMI and mortality. ¹⁵ Two cohort studies suggest that overweight children and adolescents may have increased mortality as adults. ^16,17 Childhood obesity may be a significant risk factor for adult obesity, with adolescent obesity being a better predictor than obesity at younger ages. ^8,18,19

Persons who are overweight are more likely to have adult-onset diabetes, hypertension, and risk factors for other diseases. ^8,20 The prevalence of diabetes and hypertension is 3 times higher in overweight adults than in those of normal weight. ²¹ Observational studies have established a clear association between overweight and hypercholesterolemia and suggest an independent relationship between overweight and coronary artery disease. ^{8,10,11,20-23} Being overweight has also been associated with several cardiovascular risk factors in children and adolescents, including hypercholesterolemia and hypertension. ^24-26 An elevated waist/hip circumference ratio (WHR), which may indicate central adiposity, has been shown to correlate with the presence of these conditions independent of BMI, ^27-35 and may predict the complications of obesity in adults better than BMI does. ^35,36 Obesity has also been associated with an increased risk of certain cancers (including those of the colon, rectum, prostate, gallbladder, biliary tract, breast, cervix, endometrium, and ovary), and with other disorders such as cholelithiasis, obstructive sleep apnea, venous thromboembolism, and osteoarthritis. ^8,20,37 Finally, obesity can affect the quality of life by limiting mobility, physical endurance, and other functional measures, ⁸ as well as through social, academic, and job discrimination. ^38-40

Extremely overweight individuals can be identified easily in the clinical setting by their physical appearance. More precise methods may be necessary, however, to evaluate persons who are mildly or moderately overweight. The complications of obesity occur among those with elevated body fat composition, which is most accurately measured by underwater (hydrostatic) weighing, isotopic dilution measures, and other sophisticated techniques that are not suited to clinical practice. ⁴¹ Bioelectric impedance, which provides an estimate of total body water from which the percentage of body fat can be calculated, is not widely available in clinical practice. This method has been reviewed elsewhere. ⁴²

The most common clinical method for detecting obesity is the evaluation of body weight and height based on a table of suggested or "desirable" weights. ^{e.g., 43-45} These tables generally reflect the weight at which mortality is minimized, and they only approximate the extent of fatness. The criteria for healthy body weight are a matter of controversy among experts and vary considerably as presented in different weight-for-height tables. ^46,47 Weights for children and adolescents are typically evaluated in relation to average weight for age, height, and gender. This information can be obtained from growth charts that are based on percentile distributions of body size attained at specific ages. ² An alternative measure to using weight-for-height tables or growth charts is the BMI, a weight-height index that is calculated by dividing the body weight in kilograms by the square of the height in meters (kg/m²). The BMI is easily performed, is highly reliable, ⁴⁸ and has a correlation of 0.7-0.8 with body fat content in adults. ^49-52 BMI also correlates with body fat content in children and adolescents. ^50,51,53 In adults, overweight has been defined by the National Center for Health Statistics as a BMI >= 27.8 for men and >= 27.3 for women (the 85th percentile values for persons aged 20-29 in NHANES II) ² a BMI at this level has been associated with increased risk of morbidity and mortality. ⁸ In adolescents, a BMI exceeding the 85th percentile for age and gender has been suggested as one definition for overweight ² or for those at risk of overweight. ⁵⁴

Other anthropometric methods that may be useful in the clinical setting include the measurement of skinfold thickness and the indirect assessment of body fat distribution. Skinfold thickness is a more direct measure of adiposity than BMI and correlates well with body fat content in both adults and children, but this technique requires training and has lower intra- and interobserver reliability than height and weight measurements used to calculate BMI. ^55,56 The WHR, the circumference of the waist divided by the circumference of the hips, which may be a better predictor of the sequelae associated with adult obesity than BMI, can also be measured in the clinical setting. The reliability of the WHR is comparable to that of BMI. ⁵⁷ A WHR greater than 1.0 in men and 0.8 in women has been shown to predict complications from obesity, independent of BMI, ³⁶ although the WHR has not been evaluated in all ethnic groups.

The purpose of screening for obesity is to assist the obese individual to lose or at least maintain weight and thereby prevent the complications of obesity. Such screening may also assist with counseling other patients regarding maintaining a healthy weight. Most studies of interventions for obesity involve subjects who are overweight we found no studies evaluating interventions for persons identified solely on the basis of an elevated WHR. Although there is little evidence from prospective studies that weight loss by obese individuals improves their longevity, there is evidence that obesity is associated with increased mortality ^8-13 and that weight loss in obese persons reduces important risk factors for disease and mortality. ^8,58 Prospective cohort studies ^59,60 and randomized clinical trials ^61-64,66 have demonstrated that caloric restriction or weight loss reduces systolic and diastolic blood pressures as well as the requirements for antihypertensive medication in obese adults with hypertension. These effects were independent of sodium restriction. In controlled ⁶⁷ and uncontrolled trials ^68,69 of low-calorie diets in obese diabetic patients, weight reduction was associated with improved glycemic control and reduced need for oral hypoglycemic agents and insulin. Weight loss generally improves the blood lipid profile ^70-72 and can reduce symptoms related to obstructive sleep apnea. ^73,74 To benefit from the detection of obesity, however, patients must be motivated to lose weight, must have access to an efficacious method of reducing body weight, and must maintain the resulting weight loss.

Various weight-reducing regimens are available, but many have only short-term efficacy and fail to achieve long-term weight loss. ^6,9,75,76 Research to explain the difficulty in achieving long-term weight loss is ongoing. One theory is that obesity is related to an internal "set-point" that maintains excess body fat in certain individuals. ⁷⁷ Some evidence suggests that energy expenditure decreases to compensate for reduced body weight, ⁷⁸ which would tend to return body weight to the usual weight. Such a decrease in energy expenditure could contribute to the failure of most weight-reducing regimens to achieve long-term benefits.

Dietary modification is the most commonly used weight-loss strategy, and can achieve weight reduction over the short-term in both adults and children. ^6,76,79 Very-low-calorie diets (< 800 kcal/day), which have been used for moderately to severely obese adults who have failed more conservative approaches, ⁸⁰ produce greater short-term weight loss than standard low-calorie diets of 1,000-1,500 kcal/day. ^76,79,80 Long-term results, however, are similar with both types of programs: the majority of participants eventually return to their pre-treatment weight within 5 years, ^76,79 although sustained weight loss may be achieved by some patients. ^81-85 Cohort studies and randomized controlled trials of behavioral modification, often combined with dietary therapy, have shown modest long-term benefits in adults ^86-88 and children. ^89,90 The results of the intensive dietary and behavioral interventions evaluated in these studies may not necessarily be applicable to the type of counseling likely to be given in a busy clinical primary care practice, and referral to other qualified providers or to qualified weight-management programs ¹ may be necessary to achieve similar results. The amount of weight loss that can be achieved with exercise, either alone or in combination with other methods, is relatively limited in adults ^76,91-93 and children, ^94-96 but physical activity may be beneficial in maintaining weight loss ^76,92,97,98 and reducing the WHR ^92,99 in adults. Numerous randomized clinical trials have shown that various appetite-suppressant drugs can be effective in producing short-term weight loss in adults. ^100-109 The effects, however, are limited to periods when the drug is taken, and some studies have shown a plateauing or gradual regain of weight with prolonged use. ^{76,100,101,104,105,107,110,111} Surgical techniques such as vertical band gastroplasty and gastric bypass may benefit selected adults who are morbidly obese, ^112-114 but other procedures such as intragastric balloon insertion have not been shown to be effective. ^115-118

Certain weight reduction methods may cause important adverse effects. Very-low-calorie diets can cause fatigue, hair loss, dizziness, and symptomatic cholelithiasis. ^76,119 Pharmacologic agents may cause palpitations, dizziness, insomnia, headache, and gastrointestinal discomfort. ¹²⁰ Surgical therapies such as gastroplasty and balloon insertion can lead to gastric ulceration, perforation, and bowel obstruction. ¹²¹ Some cohort studies have reported that weight change or fluctuation in weight (weight cycling) among adults is associated with increased cardiovascular morbidity and mortality, but a review by the National Task Force on the Prevention and Treatment of Obesity concluded there is insufficient evidence that weight cycling is associated with adverse effects. ¹²² There is conflicting evidence regarding the potential adverse effects of caloric restriction and weight loss on growth velocity and development in obese children and adolescents. ^123-127

The American Academy of Family Physicians, ¹²⁸ the American Heart Association, ¹²⁹ the Institute of Medicine, ¹³⁰ the American Academy of Pediatrics, ¹³¹ the Bright Futures guidelines, ¹³² and the American Medical Association guidelines for adolescent preventive services (GAPS) ¹³³ all recommend measurement of height and weight as part of a periodic health examination for patients. Bright Futures and GAPS also recommend the determination of BMI for all adolescents. ^132,133 The Canadian Task Force on the Periodic Health Examination concluded that there is insufficient evidence to recommend the inclusion or exclusion of height, weight, BMI, or skinfold measurement to screen for obesity in a routine health examination of either children or adults. ¹³⁴ The Canadian Task Force does, however, recommend measuring and plotting the height and weight of infants and children in order to identify those who are failing to thrive.

Evidence is limited that screening for obesity and implementing weight-reducing or weight maintenance strategies are effective in decreasing long-term morbidity and mortality. This is unlikely to improve in the near future due to the difficulty and cost of conducting controlled trials of weight loss with these outcome measures and of separating the effect of obesity from that of other risk factors. An additional obstacle is the low rate of long-term success in maintaining weight loss. Obesity is a chronic disorder that requires continuing treatment, which could explain the failure of short-term interventions in achieving long-term success. Although losing weight has not been proven to reduce morbidity and mortality, it is clear that weight loss reduces an individual's risk for major chronic diseases such as hypertension and coronary artery disease, and it also improves the management of both hypertension and diabetes. Periodic height and weight measurements are inexpensive, rapid, reliable, and require minimal training to perform. They may also be useful for the detection of medical conditions causing unintended weight loss or weight gain, such as cancer or thyroid disorders, and the detection of growth abnormalities in childhood. Once height and weight have been determined, the BMI or standard height and weight tables may be used as a means of evaluating adolescents and adults for obesity. In addition, determination of the WHR may be useful for assessing some adults, particularly those whose weight or BMI is borderline for classification as overweight and who have personal or family medical histories placing them at increased health risk. There are inadequate data to determine the optimal frequency of obesity screening, and this is best left to clinical discretion.

CLINICAL INTERVENTION

Periodic height and weight measurements are recommended for all patients ("B" recommendation). In adults, BMI (body weight in kilograms divided by the square of height in meters) or a table of suggested weights ^{e.g., 43-45} may be used, along with the assessment of other factors such as medical conditions or WHR, as a basis for further evaluation, intervention, or referral to specialists. In adolescents, a BMI exceeding the 85th percentile for age and gender may be used as a basis for further assessment, treatment, or referral. ⁵⁴ The height (or length if appropriate) and weight of infants and children may be plotted on a growth chart ^{e.g., 2} or compared to tables of average weight for height, age, and gender to determine the need for further evaluation, treatment, or referral. The optimal frequency for measuring height and weight in the clinical setting has not been evaluated and is a matter of clinical discretion. There is insufficient evidence to recommend for or against determination of the WHR as a routine screening test for obesity ("C" recommendation).

All patients should receive appropriate counseling to promote physical activity (see Chapter 55) and a healthy diet (see Chapter 56).

The draft update of this chapter was prepared for the U.S. Preventive Services Task Force by Barbara Albert, MD, MS, and Carolyn DiGuiseppi, MD, MPH, based in part on background papers written for the Canadian Task Force on the Periodic Health Examination by James Douketis, MD, William Feldman, MD, FRCPC, and Brenda Beagen, MA.

22. Screening for Iron Deficiency Anemia Including Iron Prophylaxis

Anemia is defined by the presence of a hemoglobin level that is below the normal range of values for the population (see Accuracy of Screening Tests ). ^1-4 U.S. populations with a high prevalence of anemia include blacks, Alaska Natives and Native Americans, immigrants from developing countries, and individuals of low socioeconomic status. ^5-7 Anemia may be due to a variety of underlying conditions. Iron deficiency is an important cause among young children and women of reproductive age in the U.S. ^8-10 The prevalence of iron deficiency anemia in U.S. children has declined in recent years ^6,11-14 and in 1993 was estimated to be at or below 3% for children aged 1-5. ¹⁵ In low-income populations and certain ethnic groups, such as Alaska Natives, the prevalence of iron deficiency anemia in children <5 years of age may be substantially higher, ranging from 10-30% (unpublished data, Centers for Disease Control and Prevention, 1993). ⁶ Among middle-class children, on the other hand, anemia is uncommon and tends to be mild (i.e., within 1% of the hematocrit level defining anemia). ^13,14 The exact prevalence of iron deficiency anemia among pregnant women is uncertain, but national data suggest that <2% of nonpregnant women aged 20-44 years have iron deficiency anemia. ⁵ Among low-income, pregnant U.S. populations, a low hemoglobin level and/or low hematocrit is present in 6% of white women and 17% of black women during the first trimester and in 25% of white women and 46% of black women during the third trimester. ⁷ The high rates of anemia in pregnant women may not be attributable to iron deficiency, however. In a large cohort of urban, low-income, mostly minority pregnant women, only 12.5% of anemic women were iron deficient. ¹⁶

As early as the 1960s, researchers demonstrated that, in general, decreased hemoglobin alone does not have readily apparent adverse effects unless it is below 10 g/dL (100 g/L). ^17-19 Clearly, persons with markedly reduced hemoglobin levels are at risk for cardiopulmonary and other complications. Reduced work productivity, endurance, and exercise capacity have been associated with anemia or iron deficiency anemia in adults, most of whom were from developing countries. ^20-26 Iron deficiency and iron deficiency anemia during infancy and early childhood have been associated with abnormal infant behavior, growth, and development, although it is unclear how much of this association is actually attributable to other factors often associated with iron deficiency (e.g., poor nutrition, low socioeconomic status). ^27-35 Hemoglobin levels well below what is considered normal for pregnancy have been associated with increased risk of low birth weight, preterm delivery, and perinatal mortality. ^16,36-42

The hemoglobin concentration and hematocrit are the principal screening tests for detecting anemia. The World Health Organization hemoglobin cut-points for diagnosing anemia in adults have been widely adopted: men, <13 g/dL menstruating women, <12 g/dL pregnant women, <11 g/dL. ¹ The Centers for Disease Control and Prevention (CDC) has also produced criteria for anemia: in infancy and childhood, <11 g/dL for 0.5-4.9 years and <11.5 mg/dL for 5.0-11.9 years in pregnancy, <11 g/dL during the first and third trimesters and <10.5 g/dL in the second trimester. ² Studies have shown that automated electronic cell counters and chemical analyzers provide accurate and reliable data on red blood cell number and size and on the concentration of hemoglobin. ^43,44 Although sampling of capillary blood is more convenient in ambulatory practice and is especially useful for infant testing, results obtained from capillary blood specimens are less reliable than those from venous blood. ^45,46 One study found the capillary microhematocrit to have a sensitivity of 90% and a specificity of 44% when compared with values obtained from venous blood with an automated cell counter. ⁴⁶

While sensitive for iron deficiency anemia, hemoglobin is not sensitive for iron deficiency because mild deficiency states may not affect hemoglobin levels. ⁴⁷ Hemoglobin is also nonspecific, since many cases of anemia are due to causes other than iron deficiency. ^9,10,16 Reported sensitivity of low hemoglobin for detecting iron deficiency ranges from 8-90% and specificity from 65-99% depending on the population, reference standard and cut-point used. ^47-50 In a national sample, detection of a hemoglobin <12 g/dL had a sensitivity of 90% and specificity of 78% for iron deficiency in black women, whereas sensitivity and specificity were 36% and 95% in white women. ⁵⁰ Other tests (i.e., total iron binding capacity, serum iron, transferrin saturation, erythrocyte protoporphyrin, mean cell volume, red blood cell distribution width, and serum ferritin) may be more accurate for the detection of iron deficiency, but they are poor screening tests for iron deficiency anemia. ^48,51-59 Among these tests, serum ferritin has the best sensitivity and specificity for diagnosing iron deficiency in anemic patients. ⁶⁰

Evidence is limited that in the asymptomatic general adolescent or adult U.S. population, early detection and treatment significantly reduces morbidity from anemia, iron deficiency, or the conditions that cause them. ^17-19,61 This evidence is further limited by the fact that studies often use inconsistent or vague definitions of anemia and iron deficiency. Observational studies in developing countries have reported decreased physical endurance and maximal exercise capacity in association with iron deficiency anemia. ^21-24,26 The extent to which this might affect daily activities that do not involve maximal exercise capacity is unknown. Clinical trials and case series from developing countries have reported conflicting results regarding a benefit of iron supplementation on work productivity in anemic or iron-deficient workers. ^22,25,62-64 There is little evidence evaluating adverse effects from the mild degree of anemia that is most often detected by screening asymptomatic persons in developed countries. In a Swedish cohort, anemic women (Hgb <12 g/dL) reported no increase in reported infections, fatigue, or other symptoms, but they were significantly more likely to report low work productivity compared to nonanemic women. ²⁰ In a small, randomized placebo-controlled trial of Welsh women with anemia (hemoglobin <10.5 g/dL) detected by population-based screening, iron therapy did not result in clinically or statistically significant improvements in psychomotor function tests, symptoms, or subjective well-being, despite increased hemoglobin concentrations. ⁶⁵ Trials evaluating the effects of iron supplementation on physiologic outcomes such as running speed and maximum running time in nonanemic, iron-depleted runners have been inconclusive. ^66,67 Although the evaluation of anemia may disclose underlying diseases (e.g., occult malignancies) that benefit from early detection, ⁶⁸ there are no data to suggest that testing for anemia is an effective means of screening for these conditions.

A number of trials have evaluated whether infants with iron deficiency anemia benefit from early treatment. Randomized controlled trials have demonstrated the efficacy of iron supplementation in correcting iron deficiency anemia in infants and children, but its effect on clinical outcomes is less clear. ^27,28,69,70 Four relatively large, generally well-conducted, randomized controlled trials in developing countries have evaluated the effects of iron supplementation on the behavior and development of anemic infants. ^27,28,31,70 Three trials failed to show a significant effect of treatment on standardized developmental test scores after short-term (6-10 days) iron therapy. ^27,28,31 In one trial, ³¹ an additional 3 months of iron therapy for all infants corrected their anemia but did not significantly improve developmental test scores. Another of the trials ²⁷ reported that after 3 months of iron therapy infants whose iron deficiency was completely corrected (36%) had developmental scores similar to iron sufficient subjects, mainly because the scores of the latter group declined. In the remaining 64%, treatment corrected anemia but not iron deficiency, and test scores remained lower in this group. This trial did not have a true placebo group, and other causes of anemia (such as vitamin A deficiency) were not adequately excluded. There was no delayed benefit of iron therapy in this trial children with hemoglobin <=10 g/dL as infants still had lower developmental scores at school entry 5 years later. ³³ The largest and most recent trial, which enrolled 12-18-month-old infants with hemoglobins <= 10.5 g/dL, reported sizable, statistically significant improvements in both mental and motor development after 4 months of oral therapy. ⁷⁰ A small randomized double-blind placebo-controlled trial ⁷¹ in the United Kingdom evaluated 2 months of iron supplementation in urban, underprivileged toddlers (aged 17-19 months) with mild to moderate anemia, using the Denver developmental screening test to assess outcome, which is not as well standardized or validated as the test used in the other trials. Effects on developmental outcomes were inconsistent, but iron supplements significantly increased rate of weight gain. Long-term results were not evaluated. It is unclear why the results of these trials differ, although adequacy and duration of therapy may account for some of the differences.

Clinical trials and a cohort study in older children have also demonstrated improved iron and hemoglobin status with therapy, ^35,69,72 but evidence for a clinical benefit from treatment of iron deficiency anemia is limited. A double-blind randomized controlled trial in 1,358 9-11-year-old Thai children failed to show any effect of iron treatment on intelligence test scores in anemic children, despite the large sample size. ⁷³ A series of small randomized controlled trials conducted in India did report small improvements in IQ with iron treatment, ^74,75 however, and two small randomized, controlled trials suggested a benefit of oral iron on some tests of learning in anemic school-aged Indonesian children. ^76,77 All of these studies suffered from important design limitations, such as use of unvalidated tests, multiple significance testing, high dropout rates, and addition of folic acid to the treatment regimen. Conflicting results have been reported concerning the effect of iron supplementation on infection rates in children. ^35,78-80 On the other hand, improved growth and weight gain with 3-6 months of iron supplementation have been reported consistently in placebo-controlled trials of anemic, malnourished children in developing countries. ^34,35,81,82 Another controlled trial reported a significant benefit from iron treatment on physical performance and submaximal work capacity in anemic Indian boys. ⁸³ It is unclear whether the results of these studies are generalizable to U.S. children, who are likely to be healthy and otherwise adequately nourished.

Early detection and treatment of iron deficiency anemia in pregnancy has been assumed to be beneficial because moderate to severe anemia (i.e., <9.0-10.0 g/dL) has been associated with a 2-3-fold increased risk of low birth weight, preterm delivery, and perinatal mortality in numerous cross-sectional and longitudinal observational studies in industrialized countries. ^16,36-42,84 The consistency of these results across different study designs and population samples is noteworthy, although such studies do not conclusively prove that anemia directly influences pregnancy outcomes. Many of the studies did not control for other factors that may have had adverse effects (e.g., smoking, maternal malnutrition), or for increases in hemoglobin and hematocrit that occur as gestation approaches term most did not differentiate iron deficiency anemia from anemia due to other causes. A large body of data suggests that iron supplements are effective in improving the hematologic indices of pregnant women, ^85-91 but there is limited evidence that improving hematologic indices in anemic women results in improved clinical outcomes for the mother, fetus, or newborn. Most published trials evaluating the effects of iron supplementation on pregnancy outcomes systematically excluded anemic women (i.e., those with hemoglobins <10 g/dL or hematocrits <=0.3) and are therefore not necessarily relevant to pregnant women with iron deficiency anemia. They are described later in the chapter (see Primary Prevention ). One controlled trial enrolled Indian women with hemoglobins as low as 7.0 g/dL who attended rural health centers, randomizing the women by health center to receive either iron and folic acid supplements for 100 days or no supplements. ⁹² The trial reported a significantly higher mean birth weight and lower rate of low birth weight infants in women who completed 100 days of supplements compared to controls. Among those receiving supplementation, the increase in birth weight was significantly related to rise in hemoglobin. A large (n = 601), retrospective cohort study from Kenya compared women with severe anemia (hemoglobin <=8.8 g/dL) who were or were not treated with ferrous sulfate. ⁹³ Treatment was associated with markedly reduced preterm delivery and stillbirth rates, and increased mean birth weight, but there was no change in neonatal death rates. Women with "mild anemia" (hemoglobin >=8.9 g/dL) who received iron therapy before 30 weeks also had lower preterm delivery and perinatal mortality rates compared to those receiving no iron or iron after 30 weeks. Neither significance testing nor adjustment for covariates was performed, limiting the conclusions that can be drawn from these data. The detection of anemia and the determination of its etiology may also lead to the discovery of other correctable obstetrical risks (e.g., poor nutritional status, medical illness) that might otherwise escape detection, but the effectiveness of anemia screening in improving outcomes related to these risks has not specifically been evaluated in developed countries.

Adverse effects of iron therapy include unpleasant gastrointestinal symptoms (e.g., nausea and constipation) that are dose-related and, at normal doses, reversible. ^94-97 Iron therapy can cause complications of excessive iron storage in patients with an underlying iron storage disorder (e.g., idiopathic hemochromatosis). ^98,99 A potential hazard of iron supplements is unintentional overdosage by children in the home 20,330 cases of ingestion of iron or iron-containing vitamins by children under 6 years, including 3 fatalities, were reported to poison control centers in 1993. ¹⁰⁰ Iron supplements accounted for 30% of fatal pediatric pharmaceutical overdoses occurring between 1983 and 1990. ¹⁰¹ Other potential adverse effects of iron mentioned in the literature (e.g., birth defects, cancer, heart disease, infection, metabolic imbalances of other minerals, and harmfully high hemoglobin levels) ¹⁰⁹ have not been proven.

Studies of the effects of iron fortification of formula and cereal on healthy, nonanemic infants have focused primarily on laboratory rather than clinical outcomes. Randomized and nonrandomized controlled trials, observational studies, and time series studies have demonstrated substantial reductions in the incidence of iron deficiency and iron deficiency anemia in healthy infants fed iron-fortified formula, iron-fortified cereal, or breast milk (with iron-fortified cereal added at 4-6 months), compared to infants fed cow's milk or unfortified formula. ^12,102-107 Evidence is more limited regarding clinical benefits from iron fortification of infant diets. A cohort study reported that infants fed iron-fortified formula beginning at age 6 months had significantly fewer diarrheal episodes compared to infants fed whole cow's milk (0.16 vs. 0.30 per child in the second 6 months of life) the incidence of other medical conditions (e.g., otitis media, dermatitis, wheezing) did not differ. ¹⁰⁶ This study did not have standardized criteria for diagnosing medical conditions and had limited control for potentially confounding variables, however. A controlled trial randomized healthy infants at a mean age of 1.3 months to either iron-fortified or nonfortified milk-based formula. ¹⁰⁸ Infants in the fortified group had a significantly greater height (by 0.9 cm) and growth rate at 12 months, but this group was also significantly taller at birth. At 12 months, there were no other statistically significant differences in clinical outcomes, such as weight, number of acute illnesses, or psychomotor development. Intake of the iron-fortified formula may have been insufficient to produce a clinical effect, however by 8 months of age, 92% of study infants and 85% of controls were drinking cow's milk rather than study formula. In another randomized controlled trial in healthy infants from very low income families, infants randomized to nonfortified formula had significantly worse psychomotor development (Bayley Scales) at 9 and 12 months of age compared to those given iron-fortified formula. ^108a Differences were no longer significant at 15 months, although sample size may have been inadequate: only half the sample was assessed at 15 months. There were no differences at any age in standardized tests of cognitive development or behavior. These results suggest a clinical benefit from iron-fortified formula, but further trials are needed to confirm these results and determine their long-term impact.

Evidence is limited that iron supplementation in healthy pregnant women with mild or no anemia results in important clinical benefits. ¹⁰⁹ Clinical trials have reported that iron supplements in healthy pregnant women with initial hemoglobins >=10 g/dL are efficacious in correcting red cell indices and iron stores, but they do not improve birth weight, length of gestation, or other outcome measures when compared to placebo or to no supplements. ^110-116 Few of these trials had sufficient statistical power to detect small positive effects of iron supplementation, however. One small randomized controlled trial in young pregnant women suggested a modest beneficial effect of routine iron supplementation on some tests of psychomotor function, but it had important discrepancies in reported data and analyses. ¹¹⁸ In a large randomized controlled trial of healthy, nonanemic pregnant women, routine iron therapy was compared to selective iron therapy given only when a confirmed hemoglobin level below 10 g/dL was detected after 14 weeks. ¹¹⁹ Women in the selective group had poorer self-reported overall health and increased rates of transfusion and operative delivery, although differences were small and may have been due to nonblinding. The routine supplementation group had more subjective side effects attributable to iron, more postdate gestations, and higher perinatal mortality the latter difference was probably attributable to chance, given small numbers and multiple comparisons. Evidence thus does not confirm important clinical benefits from routine iron supplementation in nonanemic pregnant women.

Cohort studies have reported no important adverse effects with iron-fortified formula, ^120,121 nor were serious side effects reported in the clinical trials of iron-fortified food or formula previously cited. Routine iron supplementation may produce mild, reversible gastrointestinal symptoms similar to those seen with iron therapy (see above). In one small, randomized controlled trial, oral iron supplements in iron-sufficient children resulted in significantly less weight gained after 4 months of treatment, ¹²² but additional studies are needed to confirm these results. Trials of routine iron supplementation in pregnancy have not reported adverse effects on pregnancy outcome. The doses of oral iron typically offered for routine iron supplementation (e.g., in pregnancy) are unlikely to cause complications of excessive iron storage. ^98,99 As with iron therapy, an important hazard of iron prophylaxis is unintentional overdosage by children in the home many reported cases of iron ingestion involve iron-containing prenatal vitamins. ¹⁰⁰

A number of organizations recommend some form of anemia screening during infancy and pregnancy. The Institute of Medicine (IOM), the Canadian Task Force on the Periodic Health Examination, and the Bright Futures report recommend screening high-risk infants (e.g., preterm or low birth weight, low socioeconomic status, those fed with cow's milk or nonfortified formula before 12 months of age) between 6 or 9 and 12 months of age IOM recommends screening before 3 months in preterm infants. ^15,123,124 The American Academy of Pediatrics (AAP) and the American Academy of Family Physicians (AAFP) recommend that all infants receive a hemoglobin or hematocrit measurement once during infancy the AAP recommends that it be done at or before 9 months of age. ^125,126 The recommendations of the AAFP are currently under review. Prenatal screening for anemia is recommended by the Canadian Task Force, ¹²⁷ the American College of Obstetricians and Gynecologists (ACOG), ¹²⁸ and the IOM. ¹⁵ ACOG recommends measuring a hemoglobin or hematocrit at the earliest prenatal visit and again early in the third trimester ¹²⁸ IOM recommends measuring hemoglobin once in each trimester. ¹⁵

Routine screening of older children or nonpregnant adolescents and adults is not advocated by most organizations. ^{15,124,126,128,129} Some organizations recommend screening selectively in specific high-risk populations: adolescents at increased risk due to heavy menses, chronic weight loss, nutritional deficit, or athletic activity ¹²⁴ recent immigrants from undeveloped countries ¹²⁹ the institutionalized elderly ¹²⁹ and nonpregnant women aged 15-25 or otherwise at increased risk (e.g., with large menstrual blood loss, high parity, poverty, recent immigration). ¹⁵ The AAP recommends at least one measurement of hemoglobin or hematocrit for all menstruating adolescents, preferably at age 15 years. ¹²⁵

Primary prevention of iron deficiency anemia in infancy by breastfeeding, feeding iron-fortified formula if not breastfeeding, and feeding iron-fortified cereal after 4-6 months of age, is recommended by the Canadian Task Force, ¹²³ IOM, ¹⁵ AAP, ^130,131 and Bright Futures. ¹²⁴ The AAFP recommends counseling parents of children under 6 years of age and women of childbearing age on the benefits of iron-enriched food and iron intake. ¹²⁶ The AAP recommends iron supplements in breastfed term infants who do not receive iron-fortified cereal beginning at 4 months of age. ¹³¹ The Canadian Task Force found insufficient evidence to recommend for or against the routine use of iron supplements in pregnant women. ¹²³ The IOM does not recommend routine iron supplements in nonanemic pregnant women. ¹⁵ ACOG and AAP recommend dietary supplements including iron during pregnancy if dietary intake is inadequate to meet need, or if there are other risk factors for iron deficiency. ¹²⁸

The burden of suffering from iron deficiency anemia in the general child, adolescent, and adult populations in the U.S. is low. Although it is prevalent in certain high-risk groups, mild iron deficiency anemia in the absence of symptoms appears to have only subtle health consequences in these individuals. Trials of iron therapy in school children, adolescents, and adults have not proven important clinical benefits in well-nourished populations in developed countries. Thus, there is little evidence to suggest that early detection of iron deficiency anemia in these groups is beneficial. Treatment of some forms of anemia not caused by iron deficiency (e.g., vitamin B₁₂ or folate deficiency), and some medical disorders that cause anemia, which would also be detected if hemoglobin measurement was performed routinely, can produce dramatic results. These disorders are too rare in most subgroups of the population to justify mass screening, however. There is therefore little basis for large-scale efforts to screen for anemia in the general population.

There is fair evidence to support screening for anemia in pregnant women, based on numerous observational studies reporting an association between severe to moderate anemia (hemoglobin <9-10 g/dL) and poor pregnancy outcome, and weak evidence from a nonrandomized controlled trial and a cohort study that iron treatment of anemic women improves obstetric outcomes. Women of low socioeconomic status and immigrants from developing countries, among whom iron deficiency anemia is more common, are most likely to benefit from such screening. Because hemoglobin measurement is a nonspecific test for iron deficiency, further evaluation should be performed to identify the etiology of anemia detected by screening. Serum ferritin appears to have the best sensitivity and specificity for diagnosing iron deficiency in anemic patients. Although routine iron supplementation improves hematologic indices and iron status, there is at present insufficient evidence from published clinical research to suggest that routine iron supplementation of healthy pregnant women with hemoglobins >=10 g/dL is beneficial in improving clinical outcomes for the mother, fetus, or newborn. ¹⁰⁹

The prevalence of iron deficiency anemia in the general infant population is low, and when it occurs in low-risk populations, it tends to be mild. In healthy, low-risk populations, there are few observational data showing adverse effects of iron deficiency anemia, nor have there been trials of early detection and correction of iron deficiency anemia. There is therefore little evidence to support routine hemoglobin measurement in infancy for the detection of iron deficiency anemia. On the other hand, multiple observational studies in high-risk populations (i.e., low socioeconomic status or developing countries) have found an association between iron deficiency anemia in childhood and abnormal growth and development. The largest and most recent trial ⁷⁰ of iron therapy in a high-risk population showed an important effect of iron therapy on development, while several trials in high-risk, often malnourished, infants and children have found beneficial effects of iron on growth and growth rates. In the U.S., certain infants (e.g., recent immigrants from developing countries, those of low socioeconomic status, members of certain minority and ethnic groups, preterm infants, those who begin cow's milk before 12 months) have a substantially higher prevalence of iron deficiency anemia and may also be more likely to suffer from general malnutrition. There is therefore fair evidence to support screening high-risk infants and toddlers for iron deficiency anemia, using hemoglobin (or hematocrit). As for pregnant women, evaluation to determine the etiology of anemia is appropriate. Both breastfeeding and eating iron-fortified formula and cereal are effective in the primary prevention of iron deficiency anemia. Given the absence of known adverse effects from such dietary interventions, and the other important benefits of breastfeeding (see Chapter 56), evidence supports encouraging mothers to breastfeed and to include iron-enriched foods in the diet of infants and young children.

CLINICAL INTERVENTION

A hemoglobin analysis or hematocrit is recommended for pregnant women at their first prenatal visit ("B" recommendation). There is insufficient evidence to recommend for or against repeated prenatal testing for anemia in asymptomatic pregnant women lacking evidence of medical or obstetrical complications ("C" recommendation). Screening for anemia with hemoglobin or hematocrit in high-risk infants, preferably at 6-12 months of age, is also recommended ("B" recommendation). Examples of high-risk infants include infants living in poverty, blacks, Native Americans and Alaska Natives, immigrants from developing countries, preterm and low birth weight infants, and infants whose principal dietary intake is unfortified cow's milk. Although capillary blood specimens are easier to obtain in infants, a venous blood count provides more accurate and reliable data. Serum ferritin testing may be useful as an additional screening test in selected high-risk infants. There is currently insufficient evidence to recommend for or against periodic screening for high-risk infants not found to be anemic at initial screening ("C" recommendation). There is also insufficient evidence to recommend for or against routine testing for anemia in other asymptomatic persons, but recommendations against such screening may be made on the grounds of low prevalence, cost, and potential adverse effects of iron therapy ("C" recommendation).

Guidelines for normal hemoglobin ranges for infants and pregnant women have been published. ^1-4 Appropriate hematological studies and nutrition counseling should be provided for patients found to have anemia. Compared to other diagnostic tests, serum ferritin has the best sensitivity and specificity for detecting iron deficiency in patients found to be anemic. Screening for hemoglobinopathies is discussed in Chapter 43.

Encouraging mothers to breastfeed their infants and advising parents to include iron-enriched foods in the diet of infants and young children is recommended for the primary prevention of iron deficiency anemia ("B" recommendation). There is also good evidence to recommend breastfeeding based on proven benefits unrelated to iron deficiency (see Chapter 56). Pregnant women should receive specific nutritional guidance to enhance fetal and maternal health (see Chapter 56). There is currently insufficient evidence to recommend for or against the routine use of iron supplements for healthy infants or pregnant women who are not anemic ("C" recommendation).

See the relevant background paper: U.S. Preventive Services Task Force. Routine iron supplementation during pregnancy. JAMA 1993270:2846-2854.

The draft update of this chapter was prepared for the U.S. Preventive Services Task Force by Carolyn DiGuiseppi, MD, MPH, and was based in part on a previously published background paper by the U.S. Preventive Services Task Force (review article by Steven H. Woolf, MD, MPH) and on materials prepared for the Canadian Task Force on the Periodic Health Examination by John W. Feightner, MD, MSc, FCFP.

The prevalence of elevated blood lead levels in the U.S. population has declined 78% in the past decade, ¹ due primarily to marked declines in lead in gasoline, soldered cans, and air. ^1-6 In a 1988-1991 national survey of children aged 1-5 years, 9% and 0.5% had blood lead levels >=10 micro-g/dL and >=25 micro-g/dL, respectively, down from 88% and 9% a decade before. ⁷ (The units micro-g/dL will be used throughout this chapter to convert to micro-mol/L, divide by 20.72.) Prevalence varies widely among different communities and populations, however, with studies reporting 2-41% of children having blood lead levels >=10 micro-g/dL, 0-3% >=25 micro-g/dL, and 0-0.5% >=40 micro-g/dL. ^8-19 Current national data for pregnant women have not been published, but only 0.5% of U.S. women aged 12-49 years of age have blood lead levels >=10 micro-g/dL. ⁷ Two large surveys of low-income pregnant women found 0% ²⁰ and 6% ²¹ with blood lead levels >15 micro-g/dL.

The highest mean blood lead levels in the U.S. occur in children aged 1-2 years (mean 4.1 micro-g/dL) and in adults >=50 years of age (4.0 micro-g/dL), with the lowest in adolescents (1.6 micro-g/dL). ⁷ Among adults, geometric mean levels are significantly higher in males than in females. Correlates of higher blood lead levels at all ages include minority race/ethnicity, central city residence, low income, low educational attainment, and residence in the Northeast region of the U.S. ^7,22 These factors are associated with increased exposure to important lead sources, including dilapidated, pre-1950 housing with lead-based paint, lead-soldered pipes and household lead dust and lead in dust and soil from heavy traffic and industry. ^22-27 Other potential sources of household lead exposure include clothing or waste material brought home by workers in lead-based industries or hobbies, lead-based paint and dust contamination in pre-1950 housing that is undergoing remodeling or renovation, dietary intake from lead-soldered cans and lead-based pottery, and traditional ethnic remedies. ^23,24,28

Very high levels of inorganic lead exposure can produce serious neurologic complications, which may result in death or long-term sequelae. ²³ A growing number of studies have reported associations between neurotoxic effects and blood lead levels once thought to be harmless. Adequately designed and conducted prospective cohort studies from a broad range of child populations have reported that a rise in blood lead from 10 to 20 micro-g/dL is associated with a likely decrement of about 2 points (reported range -6 to +1) in intelligence test scores (IQ). ^29-35 In these studies, the mean blood lead levels at age 1-2 years (7.7-35.4 micro-g/dL) were higher than the current U.S. mean for this age group (4 micro-g/dL), but most levels were below 35 micro-g/dL. A meta-analysis ³⁶ that included the five oldest of these cohort studies concluded that a doubling of blood lead levels from 10 to 20 micro-g/dL measured at age 2 years was associated with a statistically significant mean reduction of 1-2 IQ points evidence was inconclusive regarding an association of IQ with mean postnatal blood lead levels. Although most cross-sectional studies evaluating the association of tooth and blood lead with IQ suffer from methodologic problems such as selection bias and limited adjustment for covariates, they have been generally consistent in reporting small negative effects of elevated lead levels on IQ. [e.g., in 36, 37] A meta-analysis that included studies of whole tooth lead published since 1979 reported a statistically significant 1 point reduction in IQ associated with a doubling of tooth lead from 5 to 10 micro-g/g. ³⁶ Evidence is not sufficient to quantify the exact nature of the relationship between IQ and higher blood lead levels (i.e., 40-100 micro-g/dL). Cross-sectional studies ^38-42 have consistently reported small, inverse associations between blood or tooth lead and reaction (attentional) performance, but studies evaluating the effect of mildly elevated lead levels on other measures of neurodevelopmental function (e.g., behavior, learning disorders, auditory function) have produced inconclusive results. These have been less thoroughly evaluated than IQ, however.

In most studies, the size of the estimates of lead effects on IQ are reduced when adjusted for potentially confounding variables, ³⁶ suggesting that some of the observed association may be due to imperfectly measured or unmeasured covariates. Studies in rodents and primates, however, which can avoid most of the methodologic weaknesses of observational studies in humans, report cognitive, attentional, and behavioral deficits, as well as auditory and visual dysfunction, with mildly elevated blood lead levels, ^43-45 supporting a causal relationship between low-level lead exposure and neurotoxic effects in children. Studies demonstrating laboratory abnormalities (e.g., impaired vitamin D metabolism) in persons with blood lead levels as low as 10-15 micro-g/dL ^23,46-48 also support a causal relationship.

The effects of very high blood lead levels during pregnancy on reproductive outcomes such as abortion and stillbirth have been recognized for many years. ²³ Observational studies in pregnant women with blood lead levels <30 micro-g/dL have reported associations between elevated levels and birth weight, length of gestation (including preterm delivery), and neonatal head circumference. ^49-56 The associations have been small, variable in direction of effect, and not statistically significant in most studies. These studies failed to detect important effects on other reproductive outcomes. Inconsistent results may be due in part to imprecise measures of fetal lead exposure. ^55-59 All but one ³⁴ of six previously cited cohort studies, ^29-34 as well as the meta-analysis described above, ³⁶ reported no association between antenatal or perinatal maternal blood lead levels and full-scale IQ measured at preschool or school age. Although very high lead levels in pregnancy are clearly hazardous, the adverse effects on the fetus of antepartum lead levels in the range typically found in the U.S. are not established.

Lead exposure affects many organ systems, including cardiovascular, renal, and hepatic, but most clinically apparent (i.e., symptomatic) effects occur with blood lead levels >=50 micro-g/dL. ^23,60-63 Small increases in systolic blood pressure have been asso-ciated with mildly elevated blood lead levels (i.e., 1-3 mm Hg for a rise in blood lead from 10 to 20 micro-g/dL) in most large, population-based, cross-sectional studies evaluating nonpregnant adults and pregnant women. ^64-70 In children, evidence of blood pressure effects is more limited: one crosssectional study found no association between elevated blood lead levels (range 7-70 micro-g/dL) and elevated blood pressure. ⁷¹ Adverse effects on height from lead levels well below 40 micro-g/dL have been suggested by analyses of national cross-sectional data, ^72,73 but cohort studies with more extensive covariate adjustment report either transient or no effect of elevated lead levels (peak sample means 11-17 micro-g/dL) on growth. ^35,74,75

Screening tests considered for detecting lead exposure include blood lead and free erythrocyte (or zinc) protoporphyrin levels. Blood lead concentration is the more sensitive of the two for detecting modest lead exposure, but its accuracy, precision and reliability can be affected by environmental lead contamination during blood collection, day-to-day biologic variability, and laboratory analytic variation. Lead contamination of collecting equipment, and skin contamination during capillary sampling, may each positively bias blood lead levels by up to 1.0 micro-g/dL, on average, although individual effects of skin contamination may be much greater. ^76-80 Studies defining abnormal results as blood lead levels above 10 or 20 micro-g/dL have reported false-positive rates of 3-9% for capillary sampling compared to simultaneously collected venous blood lead. ^77-78 Day-to-day biologic variability and trends over time contribute to higher false-positive rates for initial capillary samples when compared to results from venous testing done at a later date. ^77,81 False-negative rates with capillary sampling appear to be lower, reported in one study as 1-8% compared to venous blood. ⁷⁸ In published surveys, ^76,82 80-90% of clinical laboratories participating in proficiency testing programs met performance criteria for blood lead (within +/-4 micro-g/dL of target values, for values <40 micro-g/dL ⁸² ) unpublished national data show >95% of participating laboratories meeting these criteria and >80% achieving accuracy to within +/-2 micro-g/dL of target values (unpublished data, Centers for Disease Control and Prevention, November 1993). Nonparticipating laboratories are likely to be less proficient. Reported blood lead values may differ by as much as 5 micro-g/dL from true values due to these sources of variability and bias, which may affect the predictive value of a positive test. Results from capillary samples may vary even more, although recent studies suggest the positive bias can be reduced with increased attention to reducing skin lead contamination. ^77,78

The erythrocyte protoporphyrin (EP) test, an indirect measure of lead exposure based on lead's effects on the hematopoietic system, is unaffected by contamination with environmental lead and is easily performed on capillary blood specimens, making it more acceptable for use with young patients. Erythrocyte (or zinc) protoporphyrin is insensitive, however, to modest elevations in blood lead levels. ^21,83-89 The test also lacks specificity, ^{21,83,84,86,87,90} thus limiting its predictive value. In one study, EP measurements were taken on 47,230 suburban and rural children although 4.7% of the children had an elevated erythrocyte protoporphyrin level, only 0.6% had elevated blood lead levels. ⁹¹

In communities where there is a low prevalence of lead levels requiring individual intervention with chelation or residential lead hazard control, blood lead screening will have a low yield, and many unaffected children will be tested at potentially high cost and inconvenience. A questionnaire that can predict those at high risk for elevated lead levels would allow targeted screening in low prevalence areas, increasing the yield of blood testing by increasing the pretest probability of elevated lead levels in those who are tested. Cross-sectional studies ^13-15,92-93a in urban and suburban, mostly midwestern, populations have shown that one or more positive responses to five questions (about exposures to deteriorated paint from older or renovated housing, to other lead-poisoned children, or to lead-related hobbies or industry) ¹²⁸ detects 64-87% of children with blood lead levels >=10 micro-g/dL. Three studies reported higher sensitivities (81-100%) for blood lead levels >=15-20 micro-g/dL. ^15,92,93a None of these studies evaluated the ability of questionnaires to detect levels above 20 micro-g/dL, in part because so few patients had levels so high. Specificity among the studies ranged from 32% to 75%. In the samples with a lower prevalence (2-7%) of levels >=10 micro-g/dL, the proportion of those with a negative questionnaire who had elevated blood lead levels was predictably low (0.2-3.5%), but increased to 19% when the population prevalence of elevated lead levels was higher (17-28%).

Detection of lead exposure before the development of potentially irreversible complications permits the clinician to recommend environmental interventions to limit further exposure and, when necessary, to begin medical treatment with chelating agents. Early detection may also result in interventions that prevent exposure of other children to lead (the child with elevated blood lead level acting as a sentinel for a hazardous environment). There is relatively little convincing evidence that these interventions improve health, however. One issue is that most available studies in asymptomatic children evaluate the effects of various interventions on blood lead levels rather than on clinical outcomes. Second, blood lead levels typically decline with the passage of time. On average, blood lead levels in childhood decrease with age after peaking at about 2 years of age, even without intervention. ⁷ Longitudinal studies of asymptomatic children with elevated lead levels have shown reductions in blood lead levels after short- and long-term follow-up in the absence of any intervention, ^94,95 a result attributable at least in part to regression to the mean, random variation, and laboratory error. To evaluate adequately the effects of interventions on blood lead levels, studies must take into account these changes over time, preferably by the use of controls who do not receive the intervention.

Evidence is not available to demonstrate that universal screening for blood lead results in better clinical outcomes than either screening targeted to high-risk persons or individualized testing in response to clinical suspicion. Several older studies reported that, compared to historical results from individualized testing, intensive screening programs targeted to children in high-risk neighborhoods reduced case fatality rates, mortality rates, and proportions of children detected with very high blood lead levels or who developed symptomatic lead poisoning. ^96-98 In the absence of concurrent controls, it is not clear whether the reported reductions in mortality and case fatality rates were due to screening, or to improvements in medical care over time. Reductions in mean lead levels may also have been due to secular trends, changes in screening tests, and to screening greater numbers of children, including many at low risk for severe lead poisoning. Thus, the available evidence regarding the efficacy of screening programs is weak.

In contrast to substantial evidence that chelating agents benefit children with symptomatic lead poisoning, few studies have compared potential clinical benefits of chelation therapy with its adverse effects in asymptomatic children. Ethical considerations preclude such trials for children with blood lead levels above 45 micro-g/dL. A large randomized controlled trial assessing the effect of chelation therapy on IQ in young children with venous blood lead concentrations of 20-45 micro-g/dL is currently under way (G. Rhoads, personal communication, Environmental and Occupational Health Sciences Institute, Piscataway, NJ, January 1994). An observational study ^99,100 compared children with blood lead levels between 13 and 46 micro-g/dL (median 30 micro-g/dL), who did and did not receive EDTA chelation therapy depending on the results of a lead mobilization test. There was no effect of chelation on IQ at either 7 weeks or 6 months follow-up after controlling for age and initial IQ. Changes in concentrations of blood lead, bone lead, and EP also did not differ significantly between chelated and unchelated children. The greatest reductions in blood lead were associated with the highest initial lead levels, independent of chelation. The method of treatment assignment (i.e., based on a positive mobilization test) was most likely to have biased the study toward finding an effect of chelation, yet no effect was observed. There is thus little evidence presently available to confirm a clinical benefit from chelation therapy for children with lead levels <45 micro-g/dL. A comprehensive literature review found no studies evaluating clinical effects of residential lead hazard control. Their effects on blood lead levels are reviewed below.

In uncontrolled experiments and case series in asymptomatic children with initial blood lead levels ranging from 40 to 471 micro-g/dL, chelating agents reduced blood lead levels substantially, to levels <40-70 micro-g/dL (varying with initial levels) these reductions were maintained for weeks to years after therapy was discontinued. ^101-105 Most of these children were also returned to homes that had undergone lead hazard reduction, and the effect of this additional intervention was not specifically evaluated. Chelating agents have caused short-term reductions in blood lead levels in children whose pretreatment values ranged from 20 to 49 micro-g/dL in nonrandomized comparative trials, cohort studies, and uncontrolled experiments these reductions have not been sustained over longer periods in the absence of repeated or continuing chelation therapy or environmental interventions. ^104,106-109 Most of these studies did not report whether chelation therapy was combined with environmental interventions. With such weak evidence, including the previously cited cohort study reporting no effects of chelation on IQ, ⁹⁹ it is difficult to make a convincing argument that chelation therapy to lower moderately elevated blood lead levels has a long-term benefit.

For most asymptomatic children with elevated lead levels, the primary goal of intervention is to reduce exposure to lead-contaminated paint, dust, and soil in the child's home environment, since these sources account for most excessive lead exposure. Residential lead-based paint hazard control methods have become increasingly effective for reducing exposure to lead paint and lead-contaminated dust. ^25,110,111 These new techniques are now replacing the older strategies, which often created lead dust during the intervention process, but there are currently few published studies of their effect on blood lead levels.

Because most published studies used older, less effective techniques, the effects of residential interventions on blood lead reported in the literature, and outlined below, probably indicate the minimum possible benefit of residential lead-paint and lead-contaminated dust hazard control. In an early cohort study ¹¹² of 184 children with initial blood lead levels >= 50 micro-g/dL, children discharged after chelation therapy to lead-free (i.e., new or completely gutted and renovated) housing had significantly lower mean blood lead levels when compared to children exposed to "legally abated" or to inadequately abated housing (28.8 micro-g/dL vs. 38.5 and 57 micro-g/dL, respectively). Children in lead-free housing also had fewer recurrences of levels >=50 micro-g/dL at 12 and 24-30 months follow-up. A nonrandomized trial ¹¹³ of households with children having initial blood lead levels >29 micro-g/dL compared more intensive experimental lead-reduction procedures with the lead-reduction procedures commonly in use in the study community. Neither intervention had any effect on mean dust or blood lead levels as tested 6 months after abatement, but an untreated control group was not included. Published ¹¹⁴ and unpublished ¹¹⁵ retrospective cohort studies suggest that residential lead paint hazard control is associated with modest declines (4-10 micro-g/dL) in mean blood lead levels in children with initial blood lead levels >= 25 micro-g/dL, although in one study ¹¹⁴ those with initial blood lead levels <35 micro-g/dL benefitted little from intervention. Case series and uncontrolled experiments, both weak study designs, have also evaluated lead-paint hazard control efforts in children with initial blood lead levels of 25-55 micro-g/dL ^100,116-119 several were published only as abstracts or summaries. ^115,120 These studies reported statistically significant declines in mean blood lead levels, ranging from 2.5 to 10.2 micro-g/dL, 6-12 months after residential lead-based paint hazard control. All of the studies cited suffer from important design flaws, such as substantial drop-out rates and inadequate control for confounding variables such as season and age. Despite their flaws, the consistency of the results from these studies suggests a small, beneficial effect of lead-based paint hazard control on blood lead levels. As noted, there are as yet no published studies evaluating the effects on blood lead levels of newer residential lead hazard control techniques.

There are important problems with using one-time residential lead-paint hazard control as the sole method to reduce lead exposure in children. ¹²¹ Poor, inner-city families tend to move frequently, so that treating the current residence may have limited long-term benefit to the child, although benefit may accrue to other children moving in to that residence (see below). Residential lead-paint hazard control is costly and labor-intensive, resulting in low rates of intervention, especially in poor communities. ^24,122 Lead dust is ubiquitous and highly mobile, so that recontamination by nearby lead sources, including soil lead, may occur after lead-paint hazard control efforts take place in a dwelling. ^110,123,124 These problems indicate a need for additional individual interventions, as well as more comprehensive community-based interventions, to reduce household lead exposure.

The small effect noted in studies evaluating lead-paint hazard control methods may be attributable in part to recontamination of the dwelling by nearby lead sources and from subsequent deterioration of painted surfaces. ^110,123,124 Several studies have evaluated measures designed to reduce ongoing lead-dust contamination from lead-contaminated paint and soil. In a nonrandomized controlled trial among children with blood lead levels of 30-49 micro-g/dL, having a research team wet-mop all lead-contaminated interior surfaces twice a month with a high-phosphate detergent cleanser resulted in significantly greater adjusted declines in mean blood lead levels of children in intervention households compared to children in control households (6.9 vs. 0.7 micro-g/dL) at 1-year follow-up. ¹²⁵ There have been no controlled studies to evaluate whether counseling families to perform similar cleaning would be equally effective in reducing blood lead levels. In one uncontrolled experiment, the families of 78 children with blood lead levels of 10-35 micro-g/dL, who were living in the vicinity of a defunct lead smelter, received intensive (30-45 minutes) in-home education and literature on prevention of lead exposure. ¹²⁶ The mean blood lead levels in the 51 (65%) children who had follow-up blood lead levels at 4 months declined from 15.0 to 7.8 micro-g/dL (and maximum levels from 35.0 to 12.7 micro-g/dL). Without concurrent controls, it is not possible to determine how much regression to the mean and seasonal and age variations contributed to these reductions in blood lead levels. There is also evidence that clinician counseling at the worksite to reduce lead dust ingestion by workers (e.g., through personal hygiene practices) can significantly reduce mean blood lead levels at 1-year follow-up, ¹²⁷ but this study also lacked controls and may not be generalizable to the residential setting.

A third focus of residential lead hazard control is exposure to soil lead. In a randomized controlled trial ¹²³ of young children with initial blood lead levels of 7-24 micro-g/dL, extensive soil abatement, one-time dust abatement, and removal of loose interior paint resulted in a statistically significant reduction in mean blood lead levels of 1.2-1.3 micro-g/dL compared to loose paint removal alone. This clinically insignificant decline was associated with a substantial reduction in soil lead from a median 2,000 to 105 ppm. Preliminary results of the U.S. Environmental Protection Agency's Three City Urban Soil Lead Abatement Demonstration Project similarly suggest that substantial declines in soil lead cause only modest reductions in mildly elevated blood lead concentrations. ¹²⁴ The small effect was due at least in part to rapid recontamination with dust lead in households undergoing soil abatement. Among children living near a closed lead smelter, only 3% of the variance in blood lead levels was attributable to soil lead. ^127a

An important potential benefit of residential lead hazard control is its effect on the lead levels or clinical outcomes of other children who live in the same household as a child identified with elevated lead levels, or who subsequently move into the remediated residence. The literature review revealed no published evidence evaluating the effect of residential lead hazard control measures on such children. Based on the biokinetics of lead, ²³ it is reasonable to believe that environmental interventions conducted before children are exposed are likely to prevent increases in blood lead levels more effectively than the same interventions in children who have already been exposed.

In most settings, neither residential lead-based paint or dust hazard control nor chelation therapy is routinely offered to children with blood lead levels <20 micro-g/dL, but some experts have recommended offering these children dietary counseling to reduce their blood lead levels. ¹²⁸ Diets deficient in calories, calcium, and zinc have been associated with increased gastrointestinal absorption of lead, ^129,130 but there is only limited evidence that counseling to correct such nutritional inadequacies will reduce blood lead levels or prevent further increases. Results of experimental studies of the effects of iron deficiency on lead absorption and retention in adult humans have been equivocal. ^129,131 In a cohort study of children with initial blood lead levels of 13-46 micro-g/dL, ⁹⁹ all children who were iron deficient or depleted were prescribed iron supplementation. Although most children were still iron deficient at the end of the study, there were improvements in ferritin level that were not associated with either declines in blood lead or improvements in cognitive function. Cross-sectional and cohort studies have failed to establish a clear association between mean blood lead levels and measures of iron status in women at midpregnancy or delivery, in newborns (cord blood), or in children. ^{57,99,131-134}

The most common adverse effects of screening for elevated lead levels are false-positive fingerstick results, and the anxiety, inconvenience, work or school absenteeism, and financial costs associated with return visits and repeat tests. An EDTA lead mobilization test, used for some children with blood lead levels of 30-44 micro-g/dL, ¹³⁵ requires intramuscular or intravenous infusion, a stay at the clinical center for at least 8 hours, and for young children, application of urine collection bags. ¹³⁶ Residential lead-based paint and dust hazard control, when improperly done, ²⁵ may produce acute increases in blood lead levels in resident children and abatement workers, occasionally necessitating hospitalization and chelation therapy. ^{113,116,137-139} Currently recommended techniques for lead hazard reduction are likely to reduce these adverse effects. ²⁵ Chelating agents for asymptomatic lead poisoning have also been associated with important adverse effects. EDTA and dimercaprol (BAL) have transient renal, hepatic, and other toxicity, require intravenous or intramuscular injection, and generally require hospitalization for administration. ^128,140,141 Common adverse effects of d-penicillamine are penicillin-like sensitivity reactions and transient nephrotoxicity there are rare life-threatening reactions. ^{96,105,107,128} Succimer (meso-2,3-dimercaptosuccinic acid, or DMSA) causes mild gastrointestinal and systemic symptoms, rashes, and transient elevations in liver function tests, in up to 10% of cases. ^{104,106,108,142}

Several states mandate either universal screening for lead exposure or selective screening of populations at high risk for lead exposure. ¹⁴³ Periodic screening of children with blood lead measurement is also required for Medicaid's Early and Periodic Screening, Diagnostic, and Treatment Program. ¹⁴⁴ The American Academy of Pediatrics ¹⁴⁵ and the Bright Futures guidelines ¹⁴⁶ recommend: (a) screen all children for lead exposure at about 12 months of age, and possibly again at about 24 months of age (b)take a history of lead exposure (using questionnaires provided with the guidelines) between the ages of 6 months and 6 years to identify high-risk children who should be screened earlier or more frequently and (c)provide education to parents on safe environmental, occupational, nutritional and hygiene practices to protect their children from lead exposure. Follow-up screening intervals should be based on risk assessment and previous blood lead levels. The Centers for Disease Control and Prevention (CDC) recommends screening all children at 12 months of age using a blood lead test, except in communities where no childhood lead poisoning problem exists high-risk children require earlier and more frequent screening. ¹²⁸ The American Academy of Family Physicians (AAFP) ¹⁴⁷ and the Canadian Task Force on the Periodic Health Examination ¹⁴⁸ recommend screening all children who are at high risk of lead exposure (e.g., due to exposure to heavy traffic and industry, or to dilapidated older housing). The recommendations of the AAFP are currently under review. The American Medical Association recommends regularly screening all children under the age of 6 years for lead exposure through history-taking and, when appropriate, blood lead testing. ¹⁴⁹ They recommend that the decision to employ universal or targeted screening be made based on prevalence studies of blood lead levels in the local pediatric population.

No major organizations currently recommend screening pregnant women for elevated lead levels.

There is fair evidence that screening for elevated lead levels in asymptomatic children at increased risk for lead exposure will improve clinical outcomes. Because there have been no controlled trials directly evaluating screening for elevated lead levels, this conclusion is based on a chain of evidence constructed from studies of weaker design. First, in young asymptomatic children, blood lead levels as low as 10 micro-g/dL are associated with measurable neurodevelopmental dysfunction. Second, although the national prevalence of elevated lead levels has declined substantially in the past decade, a high prevalence persists in some communities, particularly poor urban communities in the northeastern U.S. Third, measurement of venous blood lead concentration is a convenient, reliable, precise and reasonably valid screening test for assessing lead exposure. Fourth, current interventions, including residential lead hazard control and chelation therapy, can reduce blood lead levels in children identified with levels >=25 micro-g/dL, although the quality of evidence supporting their effectiveness is weak and a beneficial effect on IQ or other clinical outcomes has not yet been demonstrated. There is also weak evidence that screening high-risk children for elevated lead levels results in improved clinical outcome compared to historical controls identified by case-finding. Based on this evidence of the current burden of suffering and the effectiveness of early detection, the Task Force recommends screening children at increased risk for lead exposure.

While no studies have evaluated a specific age at which to screen, the natural history of blood lead levels in children, which increase most rapidly between 6 and 12 months and peak at age 18-24 months, suggests that screening at about 12 months of age is likely to be most effective for the early detection of elevated lead levels.

For those children who are screened and found to have initial blood lead levels <25 micro-g/dL, there is as yet little evidence regarding the effectiveness of early detection and intervention, or of repeated screening to detect further increases in blood lead. Longitudinal and cross-sectional studies suggest that in children >=2 years, most such levels will decline naturally with time, but elevated levels may persist in children who are chronically exposed. ¹⁰¹

There is no direct evidence comparing the outcomes of universal screening with the outcomes from targeted screening for elevated lead levels. Recent studies indicate that the prevalence of elevated blood levels in the U.S. has declined dramatically in the past decade, but that local prevalence is highly variable, with more than 10-fold differences between communities. In a community with a low prevalence of elevated blood lead levels, universal screening may result in disproportionate risks and costs relative to benefits. The prevalence level at which targeted screening can replace universal screening is a public health policy decision requiring consideration of factors in addition to the scientific evidence for effectiveness of early detection, such as available resources, competing public health needs, and costs and availability of alternative approaches to reducing lead exposure. Good quality analyses are needed to determine the population prevalence below which universal lead screening is not cost-effective. Clinicians can consult with their local or state health department regarding appropriate screening policy for the local child population.

In communities where data suggest that universal screening is not indicated, there may nevertheless be some children who are at increased risk of blood lead levels in the range for which individual intervention by chelation therapy or residential lead hazard control has been demonstrated to be effective. These children may have had exposure to lead sources such as lead-based hobbies or industries, traditional ethnic remedies, or lead-based pottery. Selective blood lead screening of such high-risk children is appropriate even in low prevalence communities. There is fair evidence that a validated questionnaire of known and acceptable sensitivity and specificity can identify those at high risk. In several studies, the CDC ¹²⁸ and similar questionnaires correctly identified 64% to 87% of urban and suburban children who had blood lead levels >=10 micro-g/dL. These questionnaires have not been adequately evaluated as a screening tool to detect higher blood lead levels (e.g., >=20-25 micro-g/dL), or to detect exposure in other populations (e.g., migrant workers, rural communities). Locale-specific questionnaires that inquire about likely local sources of lead exposure may lead to improved prediction.

As is the case in children, there are no controlled trials evaluating screening for elevated lead levels in pregnant women, nor are there sufficient data to construct an adequate chain of evidence demonstrating benefit. The prevalence of levels >15 micro-g/dL appears to be quite low in pregnant women. There is fair evidence that mildly elevated lead levels during pregnancy are associated with small increases in antepartum blood pressure, but limited evidence that these levels have important adverse effects on reproductive or other outcomes, including intelligence of offspring. An extensive literature search failed to identify studies evaluating screening or intervention for lead exposure in pregnant women. There are potentially important adverse effects of chelation therapy on the fetus, and of residential lead hazard control on both the pregnant woman and fetus if they are not performed according to established standards. Removal to a lead-free environment would theoretically be effective in reducing lead exposure but has not been specifically evaluated in pregnancy. There is thus insufficient evidence to recommend for or against screening pregnant women for the detection of elevated lead levels.

Population-based interventions for the primary prevention of lead exposure are likely to be more effective, and may be more cost-effective, than office-based screening, treatment and counseling. Community, regional, and national environmental lead hazard reduction efforts, such as reducing lead in industrial emissions, gasoline, and cans, have proven highly effective in reducing population blood lead levels. ^1-6,150,151 Remaining important sources of lead (e.g., lead paint and pipes in older homes, lead-contaminated soil) are, however, more difficult to address on a population-wide basis. Studies of community-based efforts to reduce lead exposure from these and other sources in order to prevent the occurrence of elevated lead levels are ongoing. ^25,110,152 Evaluation of the effectiveness of community-based interventions, and recommendations regarding their use, are beyond the scope of this document.

CLINICAL INTERVENTION

Screening for elevated lead levels by measuring blood lead at least once at age 12 months is recommended for all children at increased risk of lead exposure ("B" recommendation). All children with identifiable risk factors should be screened, as should children living in communities in which the prevalence of blood lead levels requiring individual intervention, including chelation therapy or residential lead hazard control, is high or is undefined. If capillary blood is used, elevated lead levels should be confirmed by measurement of venous blood lead. The optimal frequency of screening for lead exposure in children, or for repeated testing of children previously found to have elevated blood lead levels, is unknown and is left to clinical discretion consideration should be given to the degree of elevation, the interventions provided, and the natural history of lead exposure, including the typical peak in lead levels at 18-24 months of age.

In communities where the prevalence of blood lead levels requiring individual intervention is low, a strategy of targeted screening, possibly using locale-specific questionnaires of known and acceptable sensitivity and specificity, can be used to identify high-risk children who should have blood lead testing. Examples of individual risk factors include: (a)living in or frequently visiting an older home (built before 1950) with dilapidated paint or with recent or ongoing renovation or remodeling, (b)having close contact with a person who has an elevated lead level, (c)living near lead industry or heavy traffic, (d)living with someone whose job or hobby involves lead exposure, (e)using lead-based pottery, or (f)taking traditional ethnic remedies that contain lead. ¹²⁸ There is currently insufficient evidence to recommend an exact population prevalence below which targeted screening can be substituted for universal screening. The results of cost-benefit analyses, available resources and public health priorities are among the determinants of the prevalence below which targeted screening is recommended for a community. Clinicians can seek guidance from their local or state health department.

There is insufficient evidence to recommend for or against routine screening for lead exposure in asymptomatic pregnant women ("C" recommendation). Recommendations against such screening may be made on the grounds of limited and conflicting evidence regarding the current burden of suffering, high costs, and the potential for adverse effects from intervention.

There is insufficient evidence to recommend for or against trying to prevent lead exposure by counseling families to control lead dust by repeated household cleaning, or to optimize caloric, iron, and calcium intake specifically to reduce lead absorption ("C" recommendation). For high-risk individuals or those living in high-prevalence communities, such recommendations may be made on other grounds, including minimal risk of adverse effects from the cleaning or the dietary advice, and the additional, unrelated benefits from optimizing nutrition (see Chapter 22, Screening for Iron Deficiency Anemia, and Chapter 56, Counseling to Promote a Healthy Diet).

Recommendations regarding community- or population-based interventions for the primary prevention of lead poisoning, assessment of community lead contamination, or the setting of community priorities for lead hazard reduction, are beyond the scope of this document.

The draft update of this chapter was prepared for the U.S. Preventive Services Task Force by Carolyn DiGuiseppi, MD, MPH.

Each year in the U.S., an estimated 200,000-300,000 persons become infected with HBV, more than 10,000 require hospitalization, and 250 die of fulminant disease. ^1,2 The greatest reported incidence occurs in adults aged 20-39. ^3,4 Of note, the number of reported cases peaked in 1985 and has shown a continuous gradual decline since that time. ⁴ While most infections resolve with time, it is estimated that 1.0-1.25 million individuals have chronic, asymptomatic HBV infection (i.e., chronic carriers). ⁵ This places them at risk for developing chronic active hepatitis, cirrhosis, and primary hepatocellular carcinoma (PHC). In the population as a whole, 50-67% of acute HBV infections are asymptomatic, whereas over 90% of early childhood infections are asymptomatic. ^3,6 Individuals with asymptomatic infections are still at risk for the development of chronic HBV infection and its sequelae. An estimated 22,000 births occur to HBV-infected women each year in the U.S. ⁶ Infants whose mothers are positive for hepatitis B e antigen (HBeAg) have a 70-90% chance of becoming infected perinatally. ^6-8 Infections during infancy, while estimated to represent only 1-3% of cases, account for 20-30% of chronic infections. ⁶ The risk of developing a chronic HBV infection (i.e., carrier state) is inversely related to age at the time of infection. ^6,9,10 This risk is 85-90% for infected infants and rapidly decreases to a steady risk of 6-10% in older children and adults. The risk of developing PHC or cirrhosis depends on the length of time that an individual has been chronically infected. It is estimated that infants who become chronically infected have a 25% lifetime risk and adults have a 15% lifetime risk of PHC or cirrhosis. ³ An estimated 5,000 hepatitis B-related deaths occur each year as a result of cirrhosis and PHC, with the median age of death occurring in the fifth decade of life. ^1,11-13

The principal risk factors for HBV infection in the U.S. are injecting illicit drugs heterosexual contact with HBV-infected persons or with persons at high risk for HBV infection (e.g., injection drug users) sexual contact with multiple sex partners and male homosexual activity. ^14-17 In 1990, heterosexual activity accounted for 27% of cases, homosexual activity for 11%, and injection drug use for 14%. ¹⁵ No associated risk factor can be identified in over 30% of patients with HBV infection. ⁶ In recent years, a growing number of injection drug users have become infected currently, between 60% and 80% of persons who use illicit drugs parenterally have serologic evidence of HBV infection. ¹ In a study of inner-city pregnant women, those who presented for delivery without prenatal care, with a positive drug screen, or with a past history of any illicit drug use were at increased risk for HbsAg positivity. ¹⁸ For example, those with no prenatal care and positive urine drug screens were 29 times more likely to be seropositive than those without these risk factors. Alaska Natives, Pacific Islanders, immigrants and refugees from HBV endemic areas (including Asia, Africa, and Eastern Europe), hemodialysis patients and staff, and residents and staff in institutions for the developmentally disabled, are also at increased risk. ^1,19

The principal screening test for detecting current (acute or chronic) HBV infection is the identification of HBsAg. Immunoassays for detecting HBsAg have a reported sensitivity and specificity of greater than 98%. ^20-20d Spontaneous clearance of HBsAg occurs each year in 1% of persons with chronic HBV infection. ²¹

There is good evidence that early detection of HBsAg in pregnant women can prevent infection in the newborn. Controlled trials, ^22-30a a cohort study, ³¹ and multiple time series ^8,32,33 have shown that hepatitis B vaccine alone and in combination with hepatitis B immune globulin (HBIG) is effective in preventing the development of chronic HBV infection in infants born to HBsAg-positive mothers. Vaccine, in combination with a single dose of HBIG given within 12 hours of birth, is 75-95% efficacious in preventing chronic HBV infection, ^{22,25-27,30-31} whereas vaccine alone has an efficacy of 65-96%. ^{22,26,27,29,30a} Although the ranges of efficacy overlap, the efficacy of hepatitis B vaccine in combination with HBIG was generally greater than that of vaccine alone in studies that directly compared the two strategies, with the difference reaching statistical significance in two studies. ^24,31

In the past, prenatal testing for HBsAg was recommended only for pregnant women at high risk of having acquired HBV infection. ³⁴ Recent studies in urban and minority populations have shown that only 35-65% of HBsAg-positive mothers are identified when testing is restricted to high-risk groups. ^35-39 It is thought that many women at risk are not tested because their sexual and drug-related histories are not discussed with clinicians or because their clinicians are unfamiliar with perinatal transmission of HBV and recommended preventive measures. ⁴⁰ In addition, many women who have asymptomatic chronic HBV infection may not acknowledge having risk factors even when a careful history is taken.

Detecting acute or chronic HBV infection may also be important in preventing virus transmission to others besides newborns. Screening tests coupled with counseling have the potential to influence certain behaviors (e.g., having sex with multiple partners, sharing needles among injection drug users, donating blood products) in infected persons, and thereby prevent transmission. Sexual contacts and persons with possible percutaneous exposure may also be identified in the process and offered vaccination (see Chapter 67). The effectiveness of routine screening of asymptomatic persons in the clinical setting as a means of reducing HBV transmission needs further study, however. Routine counseling on preventive behaviors to reduce the risk of infection and transmission, and appropriate vaccination, may be more effective strategies (see Chapters 62,65, and 66).

There is little evidence that early detection of asymptomatic HBV infection reduces the risk of developing chronic liver disease or its complications. Interferon eliminates HBsAg positivity in some individuals with a diagnosis of chronic hepatitis B, ^41-45 but whether this results in a reduction in long-term morbidity and mortality has not been adequately evaluated.

A strategy of targeting high-risk populations for screening and immunizing those found to be seronegative has been ineffective in reducing the population incidence of HBV infection. ^5,16 This approach has failed as a public health strategy because a high percentage (>30%) of patients have no identifiable risk factors ⁶ and because high-risk individuals (e.g., injection drug users) may not have access to screening and vaccination services. Nevertheless, individuals known to be at high risk who are found to be seronegative on screening can be immunized and thus protected from HBV infection (see Chapters 65 and 66).

The Advisory Committee on Immunization Practices (ACIP), ⁵ the American College of Obstetricians and Gynecologists, ^46,47 the American Academy of Pediatrics, ^47,48 and the American College of Physicians (ACP) ⁴⁹ recommend that all pregnant women be tested for HBsAg during an early prenatal visit. The test may be repeated in the third trimester if acute hepatitis is suspected, an exposure to hepatitis has occurred, or the woman practices a high-risk behavior such as injection drug use. No major organizations recommend universal screening of nonpregnant individuals for HBV infection. ACIP and ACP recommend making decisions to test potential vaccine recipients for prior infection on the basis of cost-effectiveness, and state that testing in groups with the highest risk of HBV infections (i.e., HBV marker prevalence >20%) ¹ is usually cost-effective. ^1,49

Because many HBsAg-positive women are not detected during pregnancy when only high-risk women are screened, routine HBsAg testing of all pregnant women is a more effective strategy for the prevention of perinatal HBV transmission. It has been calculated that screening all of the more than four million pregnant women each year in the U.S. would detect about 22,000 HBsAg-positive mothers, and treatment of their newborns would prevent the development of chronic HBV infection in an estimated 6,000 neonates each year. ⁵⁰ Several studies have demonstrated that the long-term benefits of preventing chronic liver disease make routine prenatal HBsAg testing as cost-effective as other widely implemented prenatal and blood donor screening practices. ^39,51-53 Despite current recommendations for universal vaccination of newborns against HBV (see Chapter 65), screening all pregnant women for HBV infection is recommended as an effective intervention because the vaccine alone appears to be less efficacious than the combination of vaccine and HBIG in preventing HBV infection of infants exposed to HBsAg-positive mothers.

A recommendation for universal screening of the general population would require proof that intervention reduces the morbidity and mortality associated with asymptomatic chronic HBV infection, or that it reduces or prevents HBV transmission. While interferon therapy appears promising as an intervention, current data are insufficient to recommend its use in asymptomatic HBV-infected persons in order to improve clinical outcome. Similarly, there is little evidence to support screening and counseling seropositive persons as an effective intervention to prevent HBV transmission. Given the low burden of suffering, lack of evidence of benefit, and the costs and inconvenience associated with testing, universal screening in the nonpregnant population cannot be recommended at this time.

Routine vaccination with hepatitis B vaccine is discussed in Chapters 65 and 66. Prevaccination screening is likely to be cost-effective and should be considered in high-risk groups where the rate of previous infection is high (e.g., >20-40%), in order to avoid vaccinating immune individuals or persons with chronic HBV infections. ^54-56 In these populations, screening with antibody to hepatitis B core antigen (anti-HBc), which identifies all previously infected individuals, including those with chronic HBV infection, may be preferable. ⁵ In other high-risk adolescents and adults, routine vaccination without screening may be more cost-effective (see Chapters 65 and 66).

CLINICAL INTERVENTION

Screening with hepatitis B surface antigen (HBsAg) to detect active (acute or chronic) HBV infection is recommended for all pregnant women at their first prenatal visit ("A" recommendation). The test may be repeated in the third trimester if the woman is initially HBsAg-negative and engages in high-risk behavior such as injection drug use or if exposure to hepatitis B virus during pregnancy is suspected. Infants born to HBsAg-positive mothers should receive hepatitis B immune globulin (HBIG) (0.5 mL) intramuscularly within 12 hours of birth. Hepatitis B vaccine, at the appropriate dosage, should be administered intramuscularly concurrently with HBIG (at a different injection site). The second and third doses of vaccine should be given 1 and 6 months after the first dose. Depending on the brand of vaccine utilized, the dosage of vaccine given to an infant born to a HBsAg-positive mother may differ from that given routinely to infants born to HBsAg-negative mothers. For neonates born to women whose HBsAg-status is unknown at the time of delivery, administering vaccine within 12 hours of birth, using the same dosage as that for infants whose mothers are HbsAg-positive, is recommended. Maternal testing for HBsAg-should be performed at the same time. If the mother is found to be HBsAg-positive, HBIG should be administered to her infant as soon as possible and within 7 days of birth. Contacts (sexual or household) of HBsAg-positive pregnant women should be either vaccinated or tested to determine susceptibility to HBV and vaccinated if susceptible (see also Chapter 67). The decision to do prevaccination testing may be made based on cost-effectiveness analysis.

Routine screening for HBV infection in the general population is not recommended ("D" recommendation). There is insufficient evidence to recommend for or against routinely screening asymptomatic high-risk individuals for HBV infection in order to determine eligibility for vaccination, but recommendations for screening may be made based on cost-effectiveness analyses ("C" recommendation). Such analyses suggest that screening is usually cost-effective in groups with an HBV marker prevalence >20%. ^1,49 See Chapters 65 and 66 for further recommendations on hepatitis B vaccination and Chapter 67 for information about passive and active immunization of persons with possible exposure to HBV-infected individuals or blood products. Counseling on preventive behaviors to reduce the risk of HBV infection and transmission is discussed in Chapter 62.

The draft update of this chapter was prepared for the U.S. Preventive Services Task Force by Peter W. Pendergrass, MD, MPH, and Carolyn DiGuiseppi, MD, MPH.

About 10-15 million persons in the United States are infected with Mycobacterium tuberculosis. ¹ More than 24,000 reported cases of tuberculosis (TB) occurred in the U.S. in 1994. ^1a,2 This disease is associated with considerable morbidity from pulmonary and extrapulmonary pathology. Pulmonary symptoms are progressive and include cough, hemoptysis, dyspnea, and pleuritis. Extrapulmonary TB can involve the bones, joints, pericardium, and lymphatics, and it can cause spinal cord compression from Pott's disease. Death is more common in older patients and infants, with estimated case-fatality rates ranging from 0.3% in adolescents to 18.5% in the elderly. ³ Newborns and infants also experience significant morbidity from this disease.

The incidence of TB is greatest in Asians, Pacific Islanders, blacks, American Indians, Alaska Natives, and Hispanics. About one third of all reported cases in the U.S. occur in blacks, 20% occur in Hispanics, 14% occur in Asians and Pacific Islanders, and 1% occur in American Indians and Alaska Natives. ² About 30% of new cases occur in foreign-born immigrants. ² The prevalence in homeless persons is 1-7% for clinically active TB and 18-51% for asymptomatic M. tuberculosisinfection. ⁴

After experiencing a steady decline from 1963 to 1984, reported TB cases increased by 20% from 1985 to 1992. ² A disproportionately large number of new cases are occurring among black and Hispanic persons, among whom there was a 41% increase in reported TB cases between 1985 and 1992. ² Infection with human immunodeficiency virus (HIV) is a major contributor to the recent increase in TB cases. Persons infected with HIV are more than 100 times more likely to develop active TB than are persons with competent immune systems, and the onset of the disease is often more rapid. ⁵ Reports of multidrug-resistant TB have also increased in recent years. Nationally, the proportion of new cases resistant to both isoniazid (INH) and rifampin increased from 0.5% in 1982 to 3.3% in the first quarter of 1991. ⁶ In New York City, as many as 33% of cases are resistant to INH or rifampin. ⁷ Reported case-fatality rates in patients with multidrug-resistant TB, most of whom are infected with HIV, have been as high as 72-89% (the rate is about 30-40% for immunocompetent individuals). ⁵ The latest data indicate a 9% decrease in annually reported TB cases from 1992 to 1994, in part reflecting intensified federal, state, and local TB control efforts. ^1a

Tuberculin skin testing is the principal means of detectingM. tuberculosisinfection in asymptomatic persons. Although some authors recommend chest radiography as a first-line test in high-risk populations, ⁸ roentgenography is generally considered to be inappropriate as the initial screening test for detecting tuberculous infection in asymptomatic persons. It is important, however, as a follow-up test to identify active pulmonary TB in infected persons identified through tuberculin testing. The most accurate tuberculin skin test is the Mantoux test, in which 5 units (5 TU) of tuberculin purified protein derivative (PPD) are injected intradermally to detect delayed hypersensitivity reactions within 48-72 hours.

The frequency of false-positive and false-negative tuberculin skin tests depends on a number of variables, including immunologic status, the size of the hypersensitivity reaction, and the prevalence of atypical mycobacteria. In certain geographic areas, cross-reacting atypical mycobacteria (as well as previous BCG vaccination) can produce intermediate size reactions, thereby limiting the specificity of the test. ^9-11 False-positive results can also be produced by improper technique (e.g., measuring erythema rather than induration), hypersensitivity to PPD constituents, an Arthus reaction, and cellulitis. Prior BCG vaccination may produce false-positive indurations, but these are generally less than 10 mm in diameter. Moreover, because many BCG vaccinees either lose their immunity over time or do not convert, large indurations cannot be confidently attributed to prior BCG vaccination. ^12,13 False-negative reactions, which are estimated to occur in about 5-10% of patients, can be observed early in infection before hypersensitivity develops, in anergic individuals and those with severe illnesses (including active TB), in newborns and infants less than 3 months of age, and as a result of improper technique in handling the PPD solution, administering the intradermal injection, and interpreting the results. ¹¹ Other limitations of the Mantoux test include the time and skill required for proper administration and variability among clinicians in interpreting results. ¹⁴

Multiple puncture tests (e.g., tine, Mono-Vacc) are less expensive and easier to administer than the Mantoux test. Studies evaluating the accuracy of these devices, however, have produced inconsistent results. In general, the evidence suggests that multiple puncture tests have poor specificity and may have inadequate sensitivity when compared with the Mantoux test. ^15-17 Some of this inaccuracy is due to inconsistencies in the dose of injected tuberculin delivered by multiple puncture tests. Patient compliance can also affect the effectiveness of tuberculin skin testing because patients must return to the clinician 48-72 hours after the injection to have the test interpreted. Studies in pediatric patients report noncompliance rates of 28-82%. ^18-20

Persons who are tuberculin test negative may need repeat testing, but there are inadequate data from which to determine the optimal frequency of PPD screening. In the absence of such data, clinical decisions regarding the need for repeat testing and its frequency should be based on the likelihood of further exposure to TB and the clinician's level of confidence in the accuracy of the test results. Some negative reactions to tuberculin skin tests require immediate retesting (two-step testing) to help determine whether future positive reactions are due to the booster phenomenon or to new conversion. A positive result on the second test, typically performed 1-3 weeks later, suggests that the patient has been previously infected (boosted reaction), whereas a negative result on the second test followed by a positive result on subsequent testing suggests recent conversion. Two-step testing has become more common in screening health care workers ²¹ and other population groups (e.g., elderly nursing home residents) for tuberculous infection.

The early detection of tuberculin reactivity is of potential benefit because chemoprophylaxis with INH is an effective means of preventing the subsequent development of active TB. ²² A review of 14 controlled trials found that efficacy in preventing clinical disease ranges between 25% and 88% among persons assigned to a 1-year course of INH. ²² Among individuals who complete the course of chemoprophylaxis, efficacy is greater than 90%. ^23,24 Some studies suggest that 6 months of INH therapy in adults are nearly as effective as 12 months of treatment. ^23,26 Preventive INH therapy is also of potential public health value in preventing future disease activity and transmission of the organism to household members and other close contacts.

A number of factors, however, limit the effectiveness of INH chemoprophylaxis. Some organisms are resistant to INH and other agents. ⁵ Patient compliance with a 6-12-month regimen is often difficult. The most important limitation of INH is its potential hepatotoxicity. INH-induced hepatitis occurs in about 0.3-2.3% of patients, ²⁷ the frequency increasing with age and other factors (e.g., alcohol use). The condition can be fatal, but the exact frequency of fatal INH-induced hepatitis is uncertain. Mortality rates for persons with INH-related hepatitis were reported to be as high as 4-7% in one major study, with risk increasing directly with age (zero for persons less than 20 years of age, 0.3% for persons 20-34 years of age, 1.2% for persons 35-49 years of age, 2.3% for persons 50-64 years of age). ²⁸ These data may overestimate the actual mortality from INH-induced hepatitis because the local incidence of cirrhosis-related deaths was increased in one of the communities participating in the study. ²⁹ More recent analyses of published and unpublished data have estimated that the incidence of fatal INH-induced hepatitis is about 1-14/100,000 persons started on preventive therapy. ^30,31 The risk may be lowered by performing periodic liver function tests while patients take INH. In persons who develop complications from INH, the resulting interruption of INH therapy before completion of the 1-year course may also lower the effectiveness of TB prevention. ²⁴

Although the benefits of INH probably outweigh its side effects in persons at high risk for developing active TB (see Clinical Intervention for description of high-risk groups), it is uncertain from available data whether low-risk, asymptomatic persons with a reactive tuberculin skin test are at sufficient risk of developing TB to justify the risks of INH-induced hepatitis. Epidemiologic calculations suggest that the annual incidence of TB in a low-risk population is less than 0.1%, ^32,33 and that the lifetime probability of developing active TB ranges from 1.2% at age 20 to 0.37% at age 80. ³⁴ Depending on the risk of INH-induced hepatitis, it is possible for complications from INH treatment to be more likely than the development of TB. In the absence of definitive clinical studies to clarify this issue, investigators have used decision analysis techniques to compare the benefits and risks of INH in tuberculin skin reactors of different ages. The results of these analyses have been inconsistent. One group concluded that benefits outweigh risks until the patient exceeds age 45 ³⁵ another found that treatment was beneficial at all ages ²⁷ and another analysis concluded that INH should be withheld at all ages in the absence of other risk factors. ³⁴ A decision analysis in young adults concluded that treatment was not beneficial in this age group. ³² An analysis for elderly tuberculin skin reactors concluded that INH would neither improve nor worsen 5-year survival but would decrease the risk of developing active disease. ³³ An analysis for HIV-infected injection drug users concluded that, with the exception of black women, such patients would benefit from INH therapy even in the absence of tuberculin skin testing. ³⁶

Primary prevention through vaccination represents an alternative approach to the prevention of TB. BCG, a live vaccine derived from attenuated Mycobacterium bovis,has been used worldwide for more than 50 years to prevent TB. Clinical trials of the efficacy of BCG have yielded inconsistent results since the early 1930s, however, with reported levels of protection ranging from -56% to 80%. ^37,38 Observational studies have shown that the incidence of the disease is lower in vaccinated children than in unvaccinated controls. ^39-43 Factors contributing to the wide variation in results in BCG vaccine efficacy include genetic changes in the bacterial strains as well as differences in production techniques, methods of administration, and the populations and environments in which the vaccine has been studied. ⁴⁴ A meta-analysis of 14 trials and 12 case-control studies concluded that BCG offered 50% protection against TB overall and 64-71% protection against TB meningitis and TB-related death. ⁴⁵

The potential adverse effects of BCG vaccination include prolonged ulceration and local adenitis, which occur in about 1-10% of vaccinees. The risk varies with the type of vaccine used, the population, and the methods used to measure complications. Osteomyelitis and death from disseminated BCG infection are estimated to occur in one case per million doses administered. ⁴⁴

In the U.S., where the risk of becoming infected with M. tuberculosisis relatively low, the disease can currently be controlled most successfully by screening and early treatment of infected persons. However, BCG vaccination may have a role in the U.S. for persons with special exposures to individuals with active TB, such as uninfected children who are at high risk for continuous or repeated exposure to infectious persons who are undetected or untreated, ⁴⁴ or a future role in light of escalating multidrug resistance.

The Centers for Disease Control and Prevention (CDC), American Thoracic Society (ATS), and other members of the Advisory Committee for Elimination of Tuberculosis recommend screening the following groups for tuberculous infection: persons infected with HIV close contacts of persons with TB persons with medical risk factors associated with TB immigrants from countries with high TB prevalence medically underserved low-income populations injection drug users and residents and employees of high risk facilities. ⁴⁶ Similar recommendations have been issued by the American Academy of Family Physicians. ⁵⁵ Although the Canadian Task Force on the Periodic Health Examination recommends screening high-risk groups, it gave an "E" recommendation (good evidence against performing the maneuver in the periodic health examination) to screening low-risk persons. ^46a The American Academy of Pediatrics (AAP) recommends against routine annual skin testing of children who lack risk factors and live in low-prevalence communities. The AAP does recommend annual Mantoux testing of high-risk children, as well as consideration of less frequent periodic testing (e.g., at ages 1, 4-6, and 11-16 years) of low-risk children who live in high-prevalence communities or have unreliable histories. ⁴⁷ The Bright Futures guidelines recommend annual testing for persons of low socioeconomic status, those in high prevalence areas, those exposed to TB, and immigrants. ⁴⁸ The American Medical Association's Guidelines for Adolescent Preventive Services (GAPS) recommend annual testing for adolescents in high-risk settings including those in homeless shelters, correctional institutions, and health care facilities. ⁴⁹

Recommendations on how to perform tuberculin skin testing have been issued by the CDC and ATS. ¹¹ The CDC has recently issued guidelines on preventing transmission in health care facilities, which include specific recommendations on the categories of health care workers to include in skin-testing programs and the frequency with which they should be tested. ⁵⁰ Guidelines for the treatment of converters have been issued in a joint statement by the ATS, AAP, CDC, and Infectious Disease Society of America. ^51,52 The CDC has also issued recommendations on multidrug preventive therapy for converters with suspected contact with drug-resistant TB. ⁵ Screening certain populations for tuberculous infection is required by law in 44 states. ⁷

Recommendations on BCG vaccination have been issued in a joint statement by the Immunization Practices Advisory Committee and the Advisory Committee for Elimination of Tuberculosis. ⁴⁴ They recommended limiting BCG vaccination in the U.S. to tuberculin-negative infants and children who cannot be placed on INH and who have continuous exposure to persons with active disease, those with continuous exposure to patients with organisms resistant to INH or rifampin, and those belonging to groups with a rate of new infections greater than 1% per year and for whom the usual surveillance and treatment programs may not be operationally feasible.

CLINICAL INTERVENTION

Screening for tuberculous infection by tuberculin skin testing is recommended for all persons at increased risk of developing tuberculosis (TB) ("A" recommendation). Asymptomatic persons at increased risk include persons infected with HIV, close contacts of persons with known or suspected TB (including health care workers), persons with medical risk factors associated with TB, immigrants from countries with high TB prevalence (e.g., most countries in Africa, Asia, and Latin America), medically underserved low-income populations (including high-risk racial or ethnic minority populations), alcoholics, injection drug users, and residents of long-term care facilities (e.g., correctional institutions, mental institutions, nursing homes). The Mantoux test involves the intradermal injection of 5 units of tuberculin PPD and the subsequent examination of the injection site 48-72 hours later. Current minimum criteria for a positive skin test, based on observational data and expert opinion, are 15-mm diameter for low-risk individuals, 10-mm diameter for high-risk individuals (e.g., immigrants, medically underserved low-income populations, injection drug users, residents of long-term care facilities, persons with conditions that increase TB risk, infants, and children less than 4 years of age), and 5-mm diameter for persons at very high risk (e.g., persons infected with HIV, persons with abnormal chest radiographs, recent contacts of infected persons). Prior BCG vaccination is not currently considered a valid basis for dismissing positive results. Persons with negative reactions who are at increased risk of anergy (e.g., HIV-infected individuals) can be skin-tested for anergy, ⁵³ but this procedure is now considered optional in current CDC guidelines. ⁴⁶ Treatment decisions in HIV-infected anergic patients should be made on an individual basis. ⁵⁴ The frequency of tuberculin skin testing is a matter of clinical discretion.

Persons with a positive PPD test should receive a chest x-ray and clinical evaluation for TB. Those lacking evidence of active infection should receive INH prophylaxis if they meet criteria defined in recent guidelines. ⁵² Briefly, these criteria recommend INH prophylaxis in persons under 35 years of age who are from high-prevalence countries medically underserved, low-income, high-prevalence populations or long-term care facilities. It is also recommended in persons of any age with HIV infection or increased risk of HIV infection, other medical conditions that increase the risk of TB, or close contact with patients with newly diagnosed TB or skin test conversion. Screening for HIV infection may be indicated in recent converters (see Chapter 28). Patients with possible exposure to drug-resistant TB should be treated according to current recommendations for multidrug preventive therapy. ⁵ Directly observed therapy -- observation of the patient by a health care worker as the medication is taken -- may be indicated in patients who are unlikely to be compliant.

BCG vaccination against TB should be considered only for tuberculin-negative infants and children who cannot be placed on INH and who have continuous exposure to persons with active disease, those with continuous exposure to patients with organisms resistant to INH or rifampin, and those belonging to groups with a rate of new infections greater than 1% per year and for whom the usual surveillance and treatment programs may not be operationally feasible ("B" recommendation). These groups may also include persons with limited access to or willingness to use health care services.

The draft update of this chapter was prepared for the U.S. Preventive Services Task Force by Steven H. Woolf, MD, MPH.

Syphilis is caused by infection with the bacterium Treponema pallidumwhich can be transmitted congenitally or by sexual contact. In 1994, 20,627 cases of primary and secondary syphilis were reported in the United States. ¹ Primary syphilis produces ulcers of the genitalia, pharynx, or rectum, and secondary syphilis is characterized by contagious skin lesions, lymph-adenopathy, and condylomata lata. ² Systemic spread, including invasion of the central nervous system, can occur early in infection and may be symptomatic during early or late stages of syphilis. The disease then evolves into a latent phase in which syphilis is clinically inapparent. If left untreated, as many as one third of patients progress to have potentially severe late gummatous, cardiovascular, and neurologic complications. ³ Cardiovascular syphilis produces aortic disease (insufficiency, aneurysms, aortitis), and neurosyphilis can result in meningitis, peripheral neuropathy (e.g., tabes dorsalis), meningovascular brain lesions, and psychiatric illness. Persons with tertiary syphilis may have decreased life expectancy, and they often experience significant disability and diminished productivity as a result of their symptoms. Long-term hospitalization is often necessary for patients with severe neurologic deficits or psychiatric illness. Syphilis has been associated epidemiologically with acquisition and transmission of infection with human immunodeficiency virus (HIV). ^4,5

The incidence of syphilis has decreased by 50% since 1990, but it is still high and now approximates 1970 rates. ¹ A growing proportion of cases is being reported among commercial sex workers and persons who use illicit drugs, especially those using crack cocaine and those who exchange sex for drugs. ^6,7 There are pronounced geographic differences in the incidence of syphilis in different communities. In recent data, nearly all counties with a high incidence of reported syphilis cases (more than 10/100,000 persons) were in large metropolitan areas or in southern states nearly two thirds of all counties in the U.S. reported no cases of primary or secondary syphilis in the most recent year. ¹ The incidence of reported infections among Hispanics and blacks is 5-60 times higher than that in non-Hispanic whites. ¹ Individual communities may experience substantial fluctuations in incidence rates independent of national trends.

The incidence of congenital syphilis had increased sharply in the last 15 years, but it has fallen since 1991. ¹ Congenital syphilis results in fetal or perinatal death in 40% of affected pregnancies, as well as in an increased risk of medical complications in surviving newborns. ⁸ The incidence of congenital syphilis increased steadily in the United States from 1978 to 1991, ⁹ reaching 108 cases per 100,000 live births in 1991. ¹ (The reporting definition changed in 1989 to reflect both confirmed cases and infants at high risk of infection.) The rate dropped from 1991 to 1994, to 56 cases per 100,000 live births. ¹

Serologic tests are currently the mainstay for syphilis diagnosis and management. Nontreponemal tests are used to screen patients for the presence of nonspecific reagin antibodies that appear and rise in titer following infection. Although VDRL (Venereal Disease Research Laboratory) and RPR (rapid plasma reagin) are the most commonly used nontreponemal tests, others are available. The sensitivity of nontreponemal tests varies with the levels of antibodies present during the stages of disease. In early primary syphilis, when antibody levels may be too low to detect, results may be nonreactive, and the sensitivity of nontreponemal tests is 62-76%. ¹⁰ Antibody levels rise as disease progresses titers usually peak during secondary syphilis, when the sensitivity of nontreponemal tests approaches 100%. In late syphilis, titers decline, and previously reactive results revert to nonreactive in 25% of patients in untreated late syphilis, test sensitivity averages only 70%. ¹⁰ Nontreponemal test titers decline or revert to normal after successful treatment.

Nontreponemal tests can produce sustained or transient false-positive reactions due to preexisting conditions (e.g., collagen vascular diseases, injection drug use, advanced malignancy, pregnancy) or infections (e.g., malaria, tuberculosis, viral and rickettsial diseases), or due to laboratory-associated errors. ^10-12 The specificity of nontreponemal tests is 75-85% in persons with preexisting diseases or conditions, and it approaches 100% in persons without them. ^10,13 Because nontreponemal serodiagnostic tests may be falsely positive, all reactive results in asymptomatic patients should be confirmed with a more specific treponemal test such as fluorescent treponemal antibody absorption (FTA-ABS), which has a sensitivity of 84% in primary syphilis and almost 100% for other stages, and a specificity of 96%. ¹⁴ Two less expensive and easier to perform confirmatory tests are the MHA-TP (microhemagglutination assay for antibodies to Treponema pallidum) and HATTS (hemagglutination treponemal test for syphilis). ¹³

Treponemal tests should not be used as initial screening tests in asymptomatic patients, as they are considerably more expensive and remain reactive in patients with previous, treated infection. Used in concert with nontreponemal tests, however, the positive predictive value of treponemal tests is high, and reactive results are likely to represent true infection with syphilis. Treponemal tests may also be useful in patients with suspected late syphilis and nonreactive nontreponemal tests, since declining antibody titers may produce false-negative nontreponemal tests. All test results should be evaluated in concert with a clinical diagnosis and history.

Infection with HIV may alter the clinical presentation and performance of serologic tests for syphilis. Co-infection with HIV and syphilis does not generally impair the sensitivity of syphilis testing, although there are sporadic reports of absent or delayed response to nontreponemal tests. ^14,15 In contrast, HIV infection may reduce the specificity of syphilis testing several studies have noted increased reactivity to nontreponemal tests among HIV-infected persons without syphilis. ^15,16 Persistence of elevated nontreponemal titers after treatment for syphilis has also been reported in some HIV-infected persons, making it difficult to confirm the adequacy of treatment. ^17,18 At the same time, treponema-specific tests may become nonreactive after treatment of syphilis in HIV-infected persons, limiting the ability to document past infection. ^14,19,20

Early detection of syphilis in asymptomatic persons permits the initiation of antibiotic therapy to eradicate the infection, thereby preventing both clinical disease and transmission to sexual contacts. Antibiotic therapy with penicillin G benzathine (or tetracycline hydrochloride if neurosyphilis has been excluded) has been shown to be highly effective in eliminating T. pallidum. Early detection and penicillin treatment during pregnancy have the added benefit of reducing the risk to the fetus of acquiring congenital syphilis. ⁹ Prenatal antibiotic therapy is effective in preventing congenital syphilis when the mother is treated with penicillin early in pregnancy (desensitization for penicillin allergy may be required). ²¹ Failures can occur, however, if women are treated with erythromycin, an antibiotic with limited efficacy in preventing congenital syphilis, or if antibiotic therapy is not started until the third trimester. ²¹

The American College of Obstetricians and Gynecologists and the American Academy of Pediatrics recommend routine prenatal screening for syphilis at the first prenatal visit, after exposure to an infected partner, and in the third trimester for patients at high risk. ^22,23 In the event of incomplete or equivocal data on maternal serology or treatment, neonatal testing is recommended. The American Academy of Family Physicians ²⁴ and the American College of Physicians ²⁵ recommend serologic screening for syphilis in high-risk adults (prostitutes, persons who engage in sex with multiple partners in areas in which syphilis is prevalent, contacts of persons with active syphilis). The American Academy of Family Physicians, ²⁴ American Academy of Pediatrics, ^22,26 American Medical Association, ²⁷ and Bright Futures ²⁸ all recommend routine syphilis screening for sexually active adolescents at increased risk. The Centers for Disease Control and Prevention recommends obtaining serology for syphilis from all women at the first prenatal visit. ²¹ In communities and populations with high syphilis prevalence or for patients at high risk, serologic testing should be repeated during the third trimester and again at delivery. ²¹ The Canadian Task Force on the Periodic Health Examination recommends testing for syphilis in pregnant women and sexually active persons in high-risk groups. ²⁹

Since the annual incidence of syphilis is less than 10 cases per 100,000 persons, ¹ routine screening of the general population is likely to have low yield. Populations at increased risk due to high-risk sexual activities include commercial sex workers, persons who exchange sex for drugs, persons with other sexually transmitted diseases (STDs) including HIV, and contacts of persons with active syphilis. The value of screening for asymptomatic infection in other persons will depend on both individual risk factors (e.g., the number and nature of sex partners) and on local epidemiology. Experience with HIV and other STDs demonstrates that sexual history is not sufficiently sensitive to identify infected persons in high-risk communities some persons may not report risk factors, and even monogamous patients may be at risk from an infected partner. Conversely, in communities where syphilis is uncommon, screening asymptomatic persons is likely to detect few cases of syphilis, even when patients have high-risk behaviors.

Routine screening in both high- and low-risk areas is justified among pregnant women, because of the severe neonatal morbidity and mortality associated with congenital syphilis, as well as its potential preventability. Determination of sexual risk factors is often insensitive in pregnant women, who may be reluctant to admit some behaviors or unaware of risk factors in their partners. ¹⁰ Several studies have demonstrated that prenatal screening for syphilis is cost-effective, even when the prevalence of the disease among pregnant women is as low as 0.005%. ^30,31 Currently, congenital syphilis occurs in 0.05% of all live births. ¹

CLINICAL INTERVENTION

Routine serologic testing for syphilis is recommended for all pregnant women and for persons at increased risk for infection, including commercial sex workers, persons who exchange sex for money or drugs, persons with other STDs (including HIV), and sexual contacts of persons with active syphilis ("A" recommendation). The local incidence of syphilis in the community and the number of sex partners reported by an individual should also be considered in identifying persons at high risk of infection. The optimal frequency for such testing has not been determined and is left to clinical discretion.

All pregnant women should be tested at their first prenatal visit. For women at high risk of acquiring syphilis during pregnancy (e.g., women in the high-risk groups listed above), repeat serologic testing is recommended in the third trimester and at delivery. Follow-up serologic tests should be obtained to document decline in titers after treatment. They should be performed using the same test initially used to document infection (e.g., VDRL or RPR) to ensure comparability.

See Chapter 62 for recommendations on counseling to prevent sexually transmitted diseases.

The draft update of this chapter was prepared for the U.S. Preventive Services Task Force by James G. Kahn, MD, MPH, and A. Eugene Washington, MD, MSc.

27. Screening for Gonorrhea Including Ocular Prophylaxis in Newborns

Nearly 420,000 N. gonorrhoeae infections were reported in the U.S. in 1994 ¹ the actual number of new infections is estimated to be closer to 800,000 per year, due to incomplete reporting. ² Between 10% and 20% of untreated gonococcal infections in women lead to pelvic inflammatory disease (PID), which may require hospitalization or surgery. ³ PID is an important cause of chronic pelvic pain, ectopic pregnancy, and infertility approximately one out of four women with a prior history of PID is unable to conceive. ⁴ Pregnant women with gonococcal infections are at increased risk for obstetric complications (e.g., stillbirth, low birth weight). ^5,6 Infected women can give birth to infants with gonococcal conjunctivitis (ophthalmia neonatorum), a condition that often produces blindness if not treated. ⁵ Gonococcal infections produce urethritis, epididymitis, and proctitis in men, but few long-term complications. Disseminated gonococcal infection can cause tenosynovitis, septic arthritis, endocarditis, and meningitis, especially in persons with complement disorders.

The overall incidence of gonorrhea has steadily declined in the U.S. since 1975, ^1,7 but rates of infection have remained very high in some groups of young men and women. ⁸ Over 60% of gonococcal infections occur in persons under age 25 ⁷ adolescents (ages 15-19) have rates of infection comparable to young adults (ages 20-24). A number of demographic and behavioral characteristics are associated with higher reported rates of gonorrhea: being unmarried, urban residence, low socioeconomic status, early sexual activity, multiple sex contacts, and a prior history of gonorrhea. ^10,11 Rates of gonorrhea are highest in poor, minority communities in large cities and in the rural Southeast. Black male and female adolescents have a 10-20-fold higher rate of infection than their Hispanic or white counterparts. ^7,8,11 Geographic variation is substantial, with the highest rates of infection in the Southeastern states. ^1,7 Since most data come from public health clinics, the demographics of reported disease may not be entirely representative of the true distribution of infection.

Up to 80% of women infected with gonorrhea are asymptomatic, ¹² and asymptomatic men and women comprise an important reservoir for new infection. Nearly half of all male partners of infected women, and over three quarters of female partners of infected men, are infected. ^13,14 While the majority of infected men eventually develop symptoms, initial asymptomatic periods may last up to 45 days. ¹⁵ The prevalence of asymptomatic gonorrhea in high-risk communities is generally higher in women (4-5%) ^16,17 than in men (1.5-2.5%). ^15,18,19 Asymptomatic gonorrhea was uncommon, however, among women at a university health clinic (0.4%), ¹⁷ private practice patients in Montreal (0.4%), ²⁰ and non-Medicaid patients in Boston (<1%). ²¹ Among asymptomatic male adolescents screened at urban teen clinics or detention centers, up to 5% are infected with N. gonorrhoeae. ^22-25

The majority of pharyngeal infections are asymptomatic, but infection may be transmitted to genital sites through oral sex ²⁶ or progress to disseminated gonococcal infection. ²⁷ Pharyngeal gonorrhea, however, usually occurs in association with anogenital infection, and it responds to usual treatment regimens for anogenital gonorrhea (i.e., broad-spectrum cephalosporins and fluoroquinolones). ⁹ Persons with gonorrhea may be infected with other sexually transmitted diseases (chlamydia, syphilis, HIV) up to 50% of persons with gonorrhea have a coexistent chlamydial infection. ¹²

The frequency of antibiotic-resistant N. gonorrhoeaehas steadily increased in the U.S. Recent surveillance data estimate that 32% of gonorrhea isolates nationwide are resistant to penicillin or tetracycline. ²⁸ These organisms are currently sensitive to broad-spectrum cephalosporins such as ceftriaxone and several other antibiotics, but the emergence of new resistance remains a concern. ⁹

The most sensitive and specific test for detecting gonococcal infection in asymptomatic persons is direct culture from sites of exposure (urethra, endocervix, throat, rectum). Under quality-controlled conditions, the sensitivity of culture is high for both male and female anogenital gonorrhea, and for pharyngeal gonococcal infections. In women, a single endocervical culture is estimated to have a sensitivity of 80-95%. ^29,30 Sensitivity of cultures may be limited by inadequate clinical specimens, improper storage, transport or processing, and inhibition of growth by antibiotics in selective culture mediums. ³¹

Microscopic examination of Gram-stained urethral or cervical specimens can detect infection with N. gonorrhoeae. The sensitivity of Gram-stained urethral specimens is higher in symptomatic men (90-95%) than in asymptomatic men (70%). ³¹ The Gram stain is less sensitive for cervical infections in women (30-65%), and it is not useful for diagnosing pharyngeal or rectal infections. The specificity of stained smears is high in men (97-99%), but lower in women (90-97%), due to presence of vaginal flora. ³¹

In clinical settings where handling and storage of culture medium is difficult, other methods of testing have become increasingly popular. DNA probes and enzyme immunoassays (EIA) are currently the most widely used nonculture diagnostic tests. Compared to culture, the sensitivity, specificity, and positive predictive value (PPV) of EIA are generally high using urethral specimens from symptomatic men (>95%). ^32,33 Accuracy of EIA is significantly lower in endocervical specimens, however: sensitivity 60-100%, specificity 70-98%, and PPV 78-85%. ^32-35 Among patients in sexually transmitted disease (STD) clinics (prevalence of gonorrhea 9-10%), a DNA probe had a very high sensitivity and specificity (97-99%) and high PPV (>90%) and was more sensitive than a single culture. ^36,37 The accuracy of nonculture tests has not been adequately studied in an asymptomatic, primary care population, however. Among asymptomatic persons, in whom the prevalence of gonorrhea is often very low, a substantial proportion of positive EIA or DNA probe results may be false positives. ^32,34 Serology is neither sufficiently sensitive nor specific for use in screening. None of the nonculture tests provides information on antibiotic susceptibility.

Screening for gonorrhea in asymptomatic men has been limited by the discomfort and inconvenience of obtaining urethral specimens. ²⁴ EIA using urine specimens produces accurate results in symptomatic men, ³⁸ but when used to screen a low-prevalence population, the majority of positive EIA results have been false positives. ³⁹ Urine dipstick for leukocyte esterase (LE) is an inexpensive, rapid, and noninvasive test for urethritis in men. Among asymptomatic high-risk young men (ages 15-25, prevalence of infection 3%), urinary LE had a sensitivity of 46-60% and a specificity of 93-96% for gonorrhea. ^24,25 The PPV of LE in an asymptomatic population is low (30-43%), although some false-positive results may be due to other infections that require treatment (e.g., chlamydia).

Information from the sexual history and clinical examination have been used to improve screening strategies. In one study of 1,441 women in Boston undergoing routine pelvic examinations, five factors were independently associated with gonococcal infection: partners with gonorrhea or urethral discharge, endocervical bleeding induced by swab, age at first intercourse less than 16, payment by Medicaid (a proxy measure for low socioeconomic status), and low abdominal or pelvic pain. ²¹ The prevalence of infection among women with one or more risk factors was 2.5%, compared to 0.2% for women with no risk factors. In a second study, young age (under 20), vaginal discharge, or a sex partner suspected of having gonorrhea identified all infected women in a low-income, urban population (prevalence of gonorrhea 3%). ¹⁷

Early detection and treatment of gonococcal infection in asymptomatic persons offers the potential benefits of preventing future complications of infection, reducing transmission to uninfected partners, and identifying sexual contacts who are likely to be infected. Due to ethical considerations that preclude placebo-controlled trials of treatment, the benefits of early detection are based largely on indirect evidence: the effectiveness of antibiotic treatment and the high morbidity of untreated gonorrhea. The decline in the reported incidence of gonorrhea over the last two decades and decline in hospitalizations for PID may also indicate a benefit of current screening strategies, but other factors (increased use of condoms) have presumably had an impact as well. ⁷ Due to high rates of reinfection among those at greatest risk, screening may be of little benefit to some individuals unless it is accompanied by measures to prevent future infections. Early detection and treatment of gonorrhea during pregnancy has the potential to decrease morbidity from the obstetric complications of gonococcal infections, although this benefit has never been tested in a controlled trial.

Between 30% and 50% of infants exposed to gonococci will develop ophthalmia in the absence of treatment. ⁴⁰ Gonococcal ophthalmia can cause severe conjunctivitis and lead to corneal scarring, abscess, eye perforation, and permanent blindness. ⁴¹ Blindness due to ophthalmia neonatorum declined dramatically with the institution of widespread prophylaxis of infants with silver nitrate. Studies of ocular prophylaxis in developing countries, using historical controls, report reductions of 80-90% in the transmission of gonococcal ophthalmia neonatorum with prophylaxis with silver nitrate, tetracycline or erythromycin. ^42,43 In a U.S. study, failure rates were similar after prophylaxis with silver nitrate, erythromycin, or tetracycline (0.03-0.1%). ⁴⁴ A recent controlled trial in Kenya reported that povidone-iodine, erythromycin, and silver nitrate were each effective in preventing conjunctivitis due to N. gonorrhoeae. ⁴⁵ Tetracycline-resistant strains of gonorrhea have been reported in the U.S. and other countries. ⁴⁵ The optimal prophylactic agent against penicillinase-producing strains of N. gonorrhoeae(PPNG) has not been determined.

The Canadian Task Force on the Periodic Health Examination advises against routine screening for gonorrhea in the general population but recommends screening of high-risk patients: individuals under 30 years, particularly adolescents, with at least two sex partners in the previous year prostitutes sexual contacts of individuals known to have an STD and persons under age 16 years at first intercourse. ⁴⁶ The Centers for Disease Control and Prevention (CDC) recommends screening asymptomatic women in the following priority groups: all pregnant women, sexually active adolescents, and women with multiple sex partners. ^9,12 The American Academy of Family Physicians recommends screening prostitutes, persons with multiple sex partners or whose sex partner has multiple sex contacts, sexual contacts of persons with culture-proven gonorrhea, or persons with a history of repeated episodes of gonorrhea. ⁴⁷ These recommendations are under review. Bright Futures, ⁴⁸ the American Medical Association Guidelines for Adolescent Preventive Services (GAPS), ⁴⁹ and the American Academy of Pediatrics (AAP) ⁵⁰ recommend annual screening of sexually active adolescents. The AAP recommends dipstick urinalysis for leukocytes in all adolescents. ⁵¹ An expert panel convened in 1994 by the Institute of Medicine, National Academy of Sciences, is developing recommendations for public health strategies to control STDs, including gonorrhea.

The American College of Obstetricians and Gynecologists (ACOG) recommends obtaining endocervical cultures in pregnant women during their first prenatal visit only if they are in one of the high-risk categories for gonorrhea. ¹⁰ ACOG and CDC recommend repeating culture late in the third trimester for high-risk women. ^10,12 ACOG recommends that all cases of gonorrhea should be diagnosed or confirmed by culture to facilitate antimicrobial susceptibility testing. ¹⁰ The American Academy of Pediatrics, ⁵² American Academy of Family Physicians, ⁴⁷ and CDC ² recommend administering ointment or drops containing tetracycline, erythromycin, or 1% silver nitrate solution to the eyes of all infants shortly after birth (within 1 hour). In the absence of universal prenatal screening for gonorrhea, the Canadian Task Force also recommends universal ocular prophylaxis with any of these antibiotic agents. ⁴⁶

Gonorrhea remains an important public health problem and a major source of morbidity for women. Although definitive proof (e.g., controlled trials) that screening reduces future morbidity is not available, selective screening of high-risk women can be justified by the substantial prevalence of asymptomatic infection, the availability of accurate screening tests and effective treatments, and the high morbidity of untreated gonorrhea in women. Early identification and treatment of asymptomatic individuals is also likely to reduce transmission of gonorrhea. The benefits of early detection may be reduced by the high likelihood of reinfection unless effective measures are taken to identify and treat sex partners.

Performing routine cultures for gonorrhea on all sexually active adults would be inefficient due to the low prevalence of infection in the general population and the wide variation in the rates of gonorrhea in different communities. Clinicians must base their decision to screen for gonorrhea on both individual risk factors and the local epidemiology of disease, realizing that sexual history is often an unreliable indicator of actual risk of infection. Therefore, routine screening of all sexually active young women may be more effective in communities where gonorrhea is prevalent, while more selective screening is appropriate when the rate of infection is known to be low.

In men, the prevalence of asymptomatic infection and the morbidity from gonorrhea is much lower than in women. Asymptomatic men, however, represent an important reservoir for transmitting infection, and opportunities to identify and treat infected men are often limited. Screening asymptomatic men with currently available urine tests may generate a large proportion of false-positive results. As more reliable, noninvasive methods for testing men become available (e.g., polymerase or ligase chain reaction assays of urine), screening young men may help reduce the incidence of gonorrhea in high-risk communities. The effectiveness of such a strategy, however, deserves to be tested in a prospective study.

The primary rationale for screening all pregnant women has been the prevention of ophthalmia neonatorum. Due to the low prevalence of gonorrhea in average-risk pregnant women, and the efficacy of universal ocular prophylaxis with antibiotic ointment, the benefits of screening for gonorrhea in all pregnant women are uncertain. Screening pregnant women at high risk for gonorrhea, however, may also help prevent other complications associated with gonococcal infection during pregnancy.

CLINICAL INTERVENTION

Routine screening for gonorrhea is recommended for asymptomatic women at high risk of infection ("B" recommendation). High-risk groups include commercial sex workers (prostitutes), persons with a history of repeated episodes of gonorrhea, and young women (under age 25) with two or more sex partners in the last year. Actual risk, however, will depend on the local epidemiology of disease. Clinicians may wish to consult local health authorities for guidance in identifying high-risk populations in their community. In communities with high prevalence of gonorrhea, broader screening of sexually active young women may be warranted. Clinicians should remain alert for findings suggestive of cervical infection (e.g., mucopurulent discharge, cervical erythema or friability) during routine pelvic examinations.

Screening is recommended at the first prenatal visit for pregnant women who fall into one of the high-risk categories ("B" recommendation). An additional test in the third trimester is recommended for those at continued risk of acquiring gonorrhea. There is insufficient evidence to recommend for or against universal screening of pregnant women ("C" recommendation). Erythromycin 0.5% ophthalmic ointment, tetracycline 1% ophthalmic ointment, or 1% silver nitrate solution should be applied topically to the eyes of all newborns as soon as possible after birth and no later than 1 hour after birth ("A" recommendation).

There is insufficient evidence to recommend for or against screening high-risk men for gonorrhea ("C" recommendation). In selected clinical settings where asymptomatic infection is highly prevalent in men (e.g., adolescent clinics serving high-risk populations), screening sexually active young men may be recommended on other grounds, including the potential benefits of early treatment for preventing transmission to uninfected sex partners. Screening men with urine LE dipstick is convenient and inexpensive, but requires confirmation of positive results. Routine screening of men or women is not recommended in the general population of low-risk adults ("D" recommendation). The optimal frequency of screening has not been determined and is left to clinical discretion.

Culture of endocervical specimens is the preferred method for screening asymptomatic women. When EIA or DNA probe tests are used for initial screening, verification of positive results may be necessary, depending on the underlying risk in the patient and potential adverse consequences of a false-positive result. Treatment should employ regimens effective against penicillin- and tetracycline-resistant organisms and should include treatment for co-infection with chlamydia and treatment of sex partners. ⁹ All sexually active individuals should be counseled about effective means of preventing STDs (see Chapter 62). Clinicians should follow local gonorrhea disease-reporting requirements.

The draft update of this chapter was prepared for the U.S. Preventive Services Task Force by Mark S. Smolinski, MD, MPH, and David Atkins, MD, MPH, based in part on materials prepared for the Canadian Task Force on the Periodic Health Examination by Brenda Beagan, MSc, Elaine E. L. Wang, MD, CM, FRCPC, and Richard B. Goldbloom, MD, FRCPC.

It is estimated that 0.8-1.2 million persons in the U.S. are infected with the human immunodeficiency virus (HIV-1) and that 40,000-80,000 new infections occur each year. ^1,2 Most people infected with HIV eventually develop the acquired immunodeficiency syndrome (AIDS), defined by opportunistic infections or severe immune dysfunction. ³ Within 10 years of infection with HIV, about 50% of persons develop clinical AIDS, and another 40% or more develop other illnesses associated with HIV infection. ⁴ A small proportion (5-10%) of persons remain well 10-15 years after HIV infection, ⁵ but there is currently no available curative treatment for AIDS. Of the 476,899 cases of AIDS reported to the Centers for Disease Control and Prevention (CDC) through June 1995, 62% had died, including over 90% of those diagnosed before 1988. ⁶ HIV infection is now the leading cause of death among men ages 25-44, and the fifth leading cause of years of potential life lost before age 65. ^7,8 By the end of 1995, it is projected that there will be 130,000-205,000 persons living with AIDS in the U.S., at an annual cost of treatment in excess of $15 billion. ⁹

Men who have sex with men and injection drug users (IDUs) together accounted for over 80% of AIDS cases reported in 1994. ⁶ HIV infection is widely prevalent in these groups. ¹⁰ In seroprevalence surveys conducted in 1991-1992 at STD clinics and drug treatment facilities, the median prevalence of HIV infection among men having sex with men was 26% (range 4-47%) [a] and ranged from 2-7% among IDUs in Western cities to 12-40% among IDUs on the East Coast. ¹⁰ HIV infection is also prevalent among heterosexual persons with other STDs (median 0.6%), prisoners (range 1-15%), and residents of homeless shelters (range 1-21%). ¹⁰ Very high rates of HIV infection (up to 30%) have been detected among inner-city young adults who smoke crack, especially among women who exchange sex for drugs. ¹¹ More than 10,000 cases of AIDS have been attributed to transfusion of infected blood or blood components (i.e., clotting factor) between 1977 and 1985, but the current risk of becoming infected from blood or tissue products is extremely low. ¹²

By July 1995, over 5,900 cases of AIDS had been attributed to perinatal infection. ⁶ An estimated 0.17% of all childbearing women in the U.S. were infected with HIV in 1991-1992, but prevalence varied from 0-0.05% in 16 states to 0.6% in New York State. Of 144 urban family planning clinics conducting blinded surveillance, 13 reported a prevalence of HIV infection over 1%. ¹⁰ Of the estimated 7,000 infants born to infected mothers each year, 80% are born in 20 states where prevalence of antibody-positive newborns was 0.1% or greater. ¹³ The probability of vertical transmission from mother to infant is between 13% and 35%, ^14-16 increasing with severity of disease in the mother. ¹⁷

The distribution of new AIDS cases may not reflect the changing pattern of the HIV epidemic due to the long delay between infection and clinical AIDS. Heterosexual transmission is the most rapidly growing source of new AIDS cases, accounting for 10% of new AIDS cases in 1994 (up from 2% in 1985). ⁶ It is the leading cause of new HIV infections in American women. ^6,18 Young black and Hispanic women in large East Coast cities are at greatest risk (due to the higher prevalence of HIV in their male partners and the more efficient transmission of virus from men to women during intercourse), ¹⁹ but women of all races experienced comparable increases in heterosexually acquired AIDS cases between 1992 and 1994. ¹⁸ Large surveys in 1991-1992 of Job Corps applicants ages 16-21 (seroprevalence 0.27%), military recruits (seroprevalence 0.06%), and patients at urban hospitals (range 0.1-5.8%) indicate that the prevalence of HIV infection varies markedly among different demographic groups and geographic areas. ¹⁰ The rate of AIDS and the prevalence of HIV are substantially higher in Atlantic Coast states than in Midwest and Mountain states, in large metropolitan areas (population 500,000 or greater) than in smaller cities or rural areas, and in black and Hispanic young persons than in whites, Native Americans, or Asians/Pacific Islanders. ^6,10,20 Blinded screening of over 20,000 primary care patients in smaller cities and rural areas detected HIV in 0.15% of all patients without known disease, however. ¹⁰ The regional variations in HIV prevalence generally mirror the local prevalence of infection among drug users. IDUs account for a large proportion of new HIV infections ²¹ and are a leading source of heterosexual and perinatal transmission of HIV. ⁶

The initial screening test to detect antibodies to HIV is the enzyme immunoassay (EIA). Commercially available EIAs use antigens from whole disrupted virus (first generation), recombinant viral proteins (second generation), or chemically synthesized peptides (third generation). ²² EIA results are considered "reactive" only when a positive result has been confirmed in a second test of the original sample. In subjects with clinical AIDS, the sensitivity of EIA is close to 100%, but newly infected individuals may not develop detectable antibodies for periods of weeks to months after infection. ²³ The median interval between infection and seropositivity has been estimated at 3 months with earlier EIAs, with 95% seroconverting within 6 months. ²⁴ Estimates based on more sensitive third-generation EIAs, which may be positive within 1 week of peak antigen levels, suggest that the "window" period with current tests is substantially shorter (3-4 weeks). ^25,25a Specificity of EIA is above 99.5% with most tests. Third-generation EIAs had specificities of 99.7-99.9% when tested against uninfected controls. ^25-27 False-positive results can be caused by nonspecific reactions in persons with immunologic disturbances (e.g., systemic lupus erythematosus or rheumatoid arthritis), multiple transfusions, or recent influenza or rabies vaccination. ^28,29 Food and Drug Administration (FDA) approval has been granted to rapid tests (<15 minutes) using colorimetric assays, ³⁰ and to an EIA-based test using oral fluid samples collected with a cotton pad. ^31,32 Although these tests are sensitive and specific (>99%), neither method is recommended for the definitive diagnosis of HIV infection. ³³

To prevent the serious consequences of a false-positive diagnosis of HIV infection, confirmation of positive EIA results is necessary, using an independent test with high specificity. The Western blot (WB) is the most commonly used confirmatory test in the U.S. Indirect immunofluorescence assay (IFA), which is less expensive and less time-consuming, is also approved for confirmatory testing. ³⁴ The specificity of WB is close to 100% under controlled settings, ³⁵ but it is dependent on the skill and experience of the laboratory and on criteria used to determine positive WB results. ^33,35 The sensitivity of WB was 98.5% and specificity 92.5% in a 1989 CDC quality control survey of 140 laboratories ²⁶ most errors involved misclassification of positive or negative samples as "indeterminate." Criteria for interpreting WB have been developed to improve accuracy in clinical testing. ³⁵ Many laboratories doing a large volume of HIV testing achieved sensitivities and specificities of 100%. ³⁶

The precise false-positive rate of current HIV testing is not known. A false-positive rate of less than 1 in 100,000 was reported in experienced, centralized laboratories using careful quality control procedures. ^37,38 In practice, false-positive diagnoses can result from contaminated or mislabeled specimens, ³⁹ cross-reacting antibodies, ³³ failure to perform confirmatory tests, ⁴⁰ misinterpretation of WB patterns, or misunderstanding of reported results by clinicians or patients. ⁴¹ In one study, 8 of 900 women referred for treatment of HIV were not infected on repeat testing. ⁴⁰ To prevent errors due to mistakes in specimen handling or WB interpretation, a consensus laboratory panel recommended confirming all new diagnoses of HIV with tests on a freshly obtained specimen. ⁴²

Indeterminate WB results, due to antibody patterns that do not meet full criteria for positive test, occur in 3-8% of EIA-positive specimens. ^33,43 In a survey of over 1 million newborn specimens for maternal HIV antibody, <1 in 4,000 screened samples produced an indeterminate WB result. ^43a An indeterminate WB result may indicate evolving antibody response in recently infected subjects, but in low-risk persons it usually represents the presence of nonspecific antibodies. Follow-up of nearly 700 EIA positive/WB indeterminate blood donors documented seroconversion in only eight subjects, all but one of whom reported a high-risk behavior. ^43-45 An indeterminate WB is more significant in high-risk subjects, but the risk of seroconversion is variable (13-28%). ^44,46 Antibodies to p24 antigen were present in 29 of 30 subjects who subsequently converted. ^43,44 A new indeterminate WB in subjects who were previously seronegative is more likely to represent recent infection. ⁴⁷ Seroconversion usually occurs within 2-3 months (range 2-16 weeks in one study). ⁴⁴ A stable indeterminate WB after 6 months can be assumed to be due to nonspecific antibody reaction rather than HIV infection. ^33,48

Viral culture is the most specific test for HIV infection, but it is time-consuming, expensive, technically difficult, and insufficiently sensitive for use as a screening test. ²² Polymerase chain reaction (PCR) can detect viral genetic material in subjects who have not yet developed antibodies, but trace levels of contamination can produce false-positive results. ²² In proficiency testing of five experienced laboratories, sensitivity of PCR was 98-100% and specificity was 96-100%. ⁴⁹ With newer, more sensitive EIAs, the additional value of screening with PCR is small in adults. In over 250 high-risk persons with nonreactive EIAs, PCR detected only two confirmed cases of HIV. ^50-53 Since PCR is not 100% specific, a large proportion of positive PCR results in seronegative patients may be false positives. Despite their limitations as screening tests, viral culture, PCR, and viral antigen assays are useful for evaluating patients with symptoms of acute HIV infection.

Diagnosing infection in infants born to HIV infected mothers is difficult, since maternal antibodies to HIV are present in both infected and uninfected infants. Uninfected infants serorevert an average of 10 months after birth, but maternal antibody may persist up to 18 months. ⁵⁴ Viral culture and PCR are highly specific for infection in infants, although PCR is occasionally positive in infants who eventually serorevert and are presumed not to be infected. ⁵⁵ Reported sensitivity for culture is 60-90% ^22,56 and 84-98% for PCR, increasing after 3 months. ^57,58 Using culture and/or PCR, an estimated 50% of infected infants can be identified at birth, and up to 90% by 3 months. ⁵⁹ Other tests for perinatal infection include assays for viral antigen (sensitivity 30-60%) ^56,59 and IgA (sensitivity 50-80%). ^59,60

Patient history is an important but imperfect way to assess risk for HIV infection. Patients may conceal high-risk behaviors, and others (especially women in high-risk areas) may be unknowingly at risk from an infected sex partner. In high-prevalence family planning clinics, testing women who reported drug use or an IDU partner detected only 41-57% of all cases. ^61,62 Offering testing routinely to all women resulted in greater acceptance (up to 96%), ⁶¹ and detected 87% of all HIV infections. ⁶² Even in low-prevalence areas such as Sweden, 37% of infected pregnant women did not report clear risk factors for HIV. ⁶³ There are few data comparing the sensitivity of targeted versus routine screening in male patients. In a seroprevalence study in primary care practices, physicians were not aware of HIV risk factors in roughly one third of infected patients. ¹⁰

There is general consensus that informed consent should be obtained prior to HIV testing. ^14,64 The diagnosis of HIV has serious consequences, and compulsory testing may discourage persons from seeking care. Alternate forms of consent -- right of refusal (i.e., passive consent) versus explicit consent, active recommendation versus nondirective counseling -- have been considered to facilitate screening during pregnancy. ^13,65 Universal newborn screening without consent of the mother was considered but rejected by the New York State legislature. ⁶⁶

Half of all states require confidential reporting of HIV-infected persons by name to state or local health departments, and all require reporting of AIDS patients. ^6,67 Partner notification (contact tracing) can alert exposed persons to the need to be tested. Between 50% and 90% of sex partners can be identified through organized partner notification programs, ⁶⁸ and costs per case identified compare favorably to screening high-risk groups. ⁶⁹

In one trial, offering the option of anonymous testing resulted in higher rates of testing. ⁷⁰ Two thirds of all patients at a public clinic (and a majority of seropositive patients) chose anonymous testing over confidential testing. ⁷¹ Test kits that would allow individuals to submit specimens (blood or saliva) collected at home for anonymous testing, using coded identifiers, are being considered by the FDA. ^71a

The appropriate frequency of HIV screening is not known, but it depends in part on the incidence of new infections. Rates are highest among IDUs in Northeastern cities (3-6 infections/100 patient-years [py]), ²¹ compared to less than 1/100 py in homosexual men in most cities, ⁷² and 0.04/100 py among military personnel aged 25-29. ⁷³ Due to the low incidence of new infection and increased sensitivity of new tests, repeat testing simply to confirm an initial negative EIA is rarely indicated.

Detection of asymptomatic HIV infection permits early treatment to slow disease progression, interventions to reduce perinatal transmission, and counseling to prevent transmission of virus to uninfected sex partners or persons sharing injection needles.

Antiretroviral medications (e.g., zidovudine [ZDV or AZT], didanosine, zalcitabine) reduce mortality in AIDS patients and delay progression to AIDS in symptomatic HIV infection. ^74,75 Due to eventual resistance developed by the HIV virus, ⁷⁶ however, there is no clear benefit of initiating antiretroviral therapy (with current drugs as monotherapies) before patients become symptomatic. ^74,77,78 In an overview of six randomized, controlled trials (RCTs) of ZDV for asymptomatic HIV infection, there was no long-term benefit of early treatment versus deferred treatment (begun at onset of symptoms) on survival or progression to AIDS. ⁷⁹ For asymptomatic patients with more advanced immunodeficiency (CD4 200-500/ micro-L), early ZDV delayed progression to AIDS or AIDS-related complex over the short-term but did not improve outcomes beyond the first 1-2 years. ^74,79,80 In Concorde, the largest and longest trial -- over 1,700 men and women with asymptomatic HIV infection followed over 3 years -- there was no significant difference between patients receiving early versus deferred treatment in the combined incidence of AIDS or death (18% in each group), or in total mortality (8% and 6%, respectively). ⁸¹ The early benefits from delaying disease progression are offset by the adverse effects of ZDV (e.g., nausea, headache, and fatigue). ⁸² Early combination antiretroviral therapy, by reducing drug resistance, may be more effective than monotherapy in reducing viral burden and delaying immunodeficiency, but long-term clinical trials of these approaches have not yet been completed. ^83,84

Chemoprophylaxis can reduce the risk of Pneumocystis cariniipneumonia (PCP) in patients with more advanced immunodeficiency. The annual incidence of PCP rises to 18-25% in persons with CD4 < 200/ micro-L, ^85,86 and half of all HIV-infected persons are still asymptomatic at this stage of disease. ^85,87,88 In retrospective analyses, prophylaxis with trimethoprim-sulfamethoxazole (TMP-SMX) or inhaled pentamidine reduced the incidence of primary PCP by 67-83%, ^86,89-91 delayed onset of AIDS by 6-12 months, and prolonged survival in those with low CD4 count by almost 1 year. ^92-94 In a recent 3-year trial, TMP-SMX, dapsone, and inhaled pentamidine were equally effective as initial therapy for primary prophylaxis against PCP. ⁹⁵ TMP-SMX was more effective in shorter studies ^89,90,96 and for patients with CD4 < 100, ⁹⁵ and it is recommended as the preferred prophylactic agent ⁹⁷ long-term therapy is limited by the high incidence of side effects (e.g., leukopenia, fever, rash, or gastrointestinal side effects). TMP-SMX and dapsone also provide protection against toxoplasmosis, ^98,99 an uncommon complication of asymptomatic HIV infection in the U.S. ⁹⁵ Long-term benefits of chemoprophylaxis are limited by the continuing decline in immune function. ⁹²

HIV-infected persons infected with Mycobacterium tuberculosisare at increased risk of developing active tuberculosis, primarily at CD4 counts below 500/ micro-L. In a randomized trial among asymptomatic HIV-infected persons in Haiti, an endemic tuberculosis area, chemoprophylaxis with isoniazid reduced the incidence of tuberculosis nearly 75% and delayed progression to AIDS. ¹⁰⁰ In a U.S. cohort study, isoniazid prophylaxis reduced tuberculosis among HIV-positive, PPD-positive drug users. ^101,102 Decision analyses suggest that the benefits of prophylaxis may outweigh risks in both PPD-positive and anergic patients with HIV when exposure to tuberculosis is prevalent (e.g., in IDUs, homeless persons, and immigrants from endemic areas see Chapter 25). ¹⁰³ Chemoprophylaxis with rifabutin is also effective against Mycobacterium aviumcomplex (MAC), but few asymptomatic patients have sufficiently advanced disease (CD4 < 75/micro-L) to warrant MAC prophylaxis. ⁹⁷

There are few randomized trials of interventions in asymptomatic HIV-infected children, but TMP-SMX is safe and effective for PCP prophylaxis in other immunocompromised children. ¹⁰⁴ PCP may be the first indication that infants are infected with HIV: 44% of the children who developed PCP in one study had never been evaluated for HIV. ¹⁰⁵ Between 7% and 20% of children with HIV develop PCP within the first year of life (peak incidence between 3 and 9 months), ^105,106 and mortality is high (up to 30%). ¹⁰⁷ Adverse reactions (rash, cytopenia) from TMP-SMX occur in up to 15% of HIV-infected children. New CDC guidelines for PCP prophylaxis in infants recommend prophylaxis for all HIV- infected or possibly infected infants during the first year of life. ¹⁰⁷ Studies are currently under way to evaluate the benefit of different antiretroviral therapies in asymptomatic children.

A variety of precautions are routinely recommended for HIV-infected children and adults, due to the increased susceptibility to viral and bacterial infections: ^108-110 vaccination against influenza, pneumococcus, hepatitis B, and Haemophilus influenzae ¹¹¹ avoidance of oral (live virus) polio vaccine in children ¹¹² attention to nutrition ¹¹³ avoiding uncooked foods and high-risk sexual practices and more frequent Papanicolaou (Pap) screening for women (due to an increased risk of invasive cervical cancer). ^67,114 The benefit of these interventions in persons with asymptomatic HIV infection has not been determined.

A randomized placebo-controlled trial (ACTG 076) demonstrated that a regimen of ZDV begun between weeks 14 and 34 of pregnancy and continued through delivery and for 6 weeks in newborn infants significantly reduced perinatal HIV infection (8.3% vs. 25.5%) among infants born to seropositive mothers with mildly symptomatic HIV infection (CD4 > 200/micro-L). ¹⁶ ZDV is associated with a low incidence of severe side effects in mothers or infants, but the long-term effects on the health of infants, and on the course of HIV disease in mothers, are not known. Cesarean delivery is also associated with lower rates of vertical transmission a trial of operative versus vaginal delivery in HIV-infected pregnancies is under way in Italy. ¹¹⁵

Identifying seropositive women during pregnancy may have other important benefits: some women may be candidates for PCP prophylaxis male partners can be advised to be tested and to use condoms infants can be monitored for evidence of HIV infection and started on appropriate therapy and early involvement of social services may facilitate care for infected mothers and infants. Infected mothers are advised to avoid breastfeeding: a meta-analysis of cohort studies estimated that breastfeeding increases vertical transmission by 14%. ¹¹⁶ The extent to which early detection actually leads to these benefits is difficult to estimate. There is no clear effect of testing and counseling on fertility decisions: in two U.S. studies, pregnancy rates were similar for HIV-positive and HIV-negative women. ¹¹⁷ Infected women were more likely to choose abortion than uninfected women in one study, ¹¹⁸ but the large majority of women with HIV chose to continue the pregnancy. ⁶³

Determining whether HIV testing and counseling reduces HIV transmission is complicated by many factors: ¹¹⁹ a paucity of well-controlled trials variable quality of counseling interventions reliance on intermediate endpoints, such as self-reported changes in behavior differences between screened and unscreened patients in observational studies population-wide changes in high-risk behavior and the uncertain importance of testing versus counseling. The effect of testing and counseling varies with the specific behavior and population being targeted. ¹¹⁷ Programs that targeted couples in which one member was infected provide the strongest evidence of the benefits of testing and counseling: compared with historical controls, counseled couples increased regular condom use and significantly reduced the rate of seroconversion in partners. ^120-123

Among homosexual men, high-risk sexual practices and new HIV infections have declined substantially since the development of HIV tests. Community-wide changes may have been more important than identification of seropositive persons, however, and there are worrisome signs of persisting unsafe practices among younger gay men. ¹²⁴ Condom use is generally higher among seropositive men than seronegative or untested men, but longitudinal studies suggest increasing use of condoms across all groups. ^125-127 Unprotected anal intercourse and number of sex partners have declined over time in both tested and untested men. The absolute change in risk may be greater in seropositive men, who engage in higher-risk behavior at baseline. ¹²⁸ A substantial proportion of seropositive men continue to have sex with multiple partners and engage in oral intercourse 5-15% continue unprotected anal intercourse. ¹²⁸

The effects of screening in injection drug users are less consistent. Among drug users in treatment, drug use and needle sharing decline after HIV counseling and testing but also declined among unscreened patients. ^117,129 In a community survey, IDUs who had received testing and counseling were half as likely to share needles as untested subjects. ¹³⁰ Testing has inconsistent effects on high-risk sexual behavior among drug users. Seropositive IDUs are more likely to report condom use in some cross-sectional studies, but 30-70% use condoms only occasionally or not at all. ^117,131

Counseling and testing patients at STD clinics has had variable results. Rate of recurrent STDs was unchanged 1 year after testing in one study, ¹³² was lower among HIV-positive than HIV-negative subjects in another (15% vs. 23%), ¹³³ and declined among seropositive patients while rising among seronegative patients in a third. ¹³⁴ In one randomized trial, testing and counseling reduced unprotected intercourse more than counseling alone. ¹³⁵ Other longitudinal studies suggest little change in sexual behavior in seronegative subjects after testing and counseling. Routine testing and counseling among students at a college health clinic did not improve low rates of condom use. ¹³⁶ Among women tested in community health clinics, seronegative women did not reduce sexual risk factors after testing and counseling, compared with untested controls. ¹³⁷

Efforts to modify high-risk behaviors in infected and high-risk persons are often hindered by substance abuse, poverty, limited education, denial, or economic necessity (i.e., prostitutes). A minority of seropositive persons abstain completely from sex or drug use after diagnosis. Those who do not may have trouble obtaining condoms or clean needles but may not inform sex partners that they are infected. ¹³⁸ Female partners of infected men may minimize risk or be unable to get their male partner to consistently use a condom. ¹³⁹

The diagnosis of HIV infection can have significant adverse effects, among them intense anxiety, depression, somatization, or anger. ^140,141 Among 1,718 newly diagnosed patients with HIV, 21% met criteria for depression at first visit, but psychological distress was related more to symptoms than diagnosis and diminished with time. ¹⁴² Testing reduces anxiety in high-risk persons who are seronegative. Despite recent efforts to improve public perceptions and attitudes, the stigma associated with the diagnosis of HIV/AIDS is still significant. ¹⁴³ Disclosure of test results can result in disrupted personal relationships, domestic violence, social ostracism, and discriminatory action, such as loss of employment, housing, health insurance, and educational opportunities. ¹⁴⁴ Recent legislation and the expanded case definitions for AIDS may help prevent some forms of discrimination and help ensure medical care for those with more advanced infection. Information on the frequency or consequences of false-positive diagnoses are largely anecdotal. Although retesting and follow-up can resolve most errors, misdiagnosis may cause irreparable harm (divorce, abortion, etc.). Finally, negative test results may provide false reassurance unless patients are counseled about their continuing risk of infection from drug use and high-risk sexual activity.

Counseling and HIV testing of high-risk individuals are recommended by the CDC ¹⁴ and numerous medical organizations: the Canadian Task Force on the Periodic Health Examination (CTF), ¹⁴⁵ the American Academy of Family Physicians, ¹⁴⁶ the American Medical Association (AMA), ¹⁴⁷ the American College of Obstetricians and Gynecologists (ACOG), ¹¹⁴ the American College of Physicians, and the Infectious Disease Society of America. ¹⁴⁸ High-risk individuals include men who have sex with men persons seeking treatment for STDs injection drug users and their sex partners recipients of transfusion between 1978 and 1985 and persons who have had multiple sex partners or exchanged sex for money or drugs. Bright Futures ¹⁴⁹ and the AMA Guidelines for Adolescent Preventive Services (GAPS) ¹⁵⁰ recommend offering HIV testing to all at-risk adolescents, including those with more than one sex partner in the last 6 months.

The CDC recommends that health care facilities where the prevalence of infection exceeds 1%, or the AIDS diagnosis rate is greater than 1/1,000 hospital discharges, consider routine, voluntary screening among patients aged 15-54 years. ¹⁵¹ The AMA approves of routine HIV testing in the clinical setting, based on local considerations such as planned medical procedures and local seroprevalence. ¹⁴⁷ GAPS ¹⁵⁰ and AAFP ¹⁴⁶ recommend offering screening to sexually active adolescents and adults from high-prevalence communities.

The U.S. Public Health Service (PHS) released new guidelines in 1995, recommending that all pregnant women be routinely counseled and encouraged to have HIV testing. ¹⁵² Similar policies have been approved by American Academy of Pediatrics (AAP) ⁶⁵ and ACOG. ¹⁵³ Pregnant women should be screened as soon as the woman is known to be pregnant repeat testing may be indicated near delivery for women at high risk of infection. The CTF (prior to ACTG 076) concluded there was insufficient evidence to recommend for or against routine screening in pregnancy, due to the low rate of infection in Canada. ¹⁴⁵ In cases where the HIV serostatus of the mother is not known, PHS and AAP guidelines suggest that health care providers educate the mother about benefits to her infant and encourage her to allow testing for the newborn. ^65,152 A 1991 Institute of Medicine task force (before ACTG 076) recommended voluntary screening of all pregnant women in high-prevalence areas and of high-risk women in other areas, but it found insufficient evidence to recommend routine newborn screening. ⁶⁴

Both the AMA and the AAP have endorsed alternate procedures for pretest counseling and consent, including right of refusal, to facilitate routine testing in specific situations. Mandatory testing for HIV is currently required on entrance to the military, and for donors of blood, organs, and tissue federal prisoners and persons seeking to immigrate to the U.S. Individual state laws vary regarding mandatory testing, confidentiality of results, informed consent, and reporting of seropositive persons to public health officials. ⁶⁷ The CDC recommends that seropositive persons be instructed how to notify their partners, but suggests that physicians or health department personnel should use confidential procedures to ensure that partners are notified. ¹⁴

Early detection of asymptomatic HIV infection can reduce morbidity and mortality in infected persons, but the long-term benefits are currently limited by the relentless course of disease in most patients. The most compelling argument for early detection is the potential to prevent transmission of HIV, which may occur over many years before infected persons develop symptoms of HIV infection. Although there is only indirect evidence that screening reduces the incidence of new HIV infections, even small changes in transmission will have important public health benefits.

Screening is most important in the high-risk groups that currently account for the large majority of AIDS cases and new HIV infections. ¹⁵⁴ The ability of ZDV to reduce perinatal transmission of HIV provides strong evidence of the benefit of screening during pregnancy. In high-risk communities, offering HIV testing to all pregnant women is more acceptable to patients, easier to implement, and more sensitive than screening on the basis of self-reported risk factors. In areas where HIV infection is uncommon, however, the choice between targeted screening and universal screening is a policy decision. Universal screening may detect occasional cases of HIV infection among women without reported risk factors, but it will subject many women at negligible risk to the potential harms from a false-positive or indeterminate test result. If specificity of testing is 99.98%, routine screening in low-risk populations (e.g., pregnant women in low-prevalence states) will generate one false-positive and many additional indeterminate results for every true-positive. Although indeterminate and false-positive results can generally be resolved with follow-up testing, some women may decide to terminate the pregnancy before infection status can be definitively determined. Counseling and testing many thousands of low-risk women to detect a single case of HIV may also divert resources from more important issues. If routine testing can be provided with the combination of accuracy and low costs achieved by large, centralized screening programs, ^37,63,155 the justification for universal screening would be stronger.

A growing number of HIV infections occur in persons who are infected through heterosexual contact. The risk of heterosexual transmission varies widely among different communities, with the highest risk among poor minority women in large cities and the rural South. In high-risk communities or clinics, routine screening of sexually active young women and men may be appropriate. In populations where prevalence of infection is low, more selective screening is likely to be more efficient: 5% of women and 12% of men report multiple sex partners within the last 12 months without consistent condom use. ¹⁵⁶ Deciding what constitutes a "high-risk" community is a policy decision, ⁶⁴ depending in part on available data and resources for testing. A prevalence of 1/1,000 among newborns, ¹⁵⁷ or an AIDS diagnosis rate of more than 1/1,000 hospital discharges, ¹⁵¹ has been used to justify routine screening in other settings. Community prevalence provides only a crude measure of individual risk, however, and should not replace careful assessment of high-risk behaviors in each patient.

Screening for HIV in high-risk groups is cost-effective under a wide range of assumptions. In an analysis of federally funded programs (where HIV prevalence was 2.6%) testing and counseling activities saved money even if only one new infection is avoided for every 100 seropositive subjects identified. ¹⁵⁸ In Sweden, where prevalence of infection is only 0.01% in pregnant women, routine prenatal HIV testing costs approximately $10 per patient and $100,000 per case identified. ⁶³ Screening is less cost-effective in asymptomatic adults if only the benefits from early treatment are considered. ¹⁵⁴ Revised cost-effectiveness analyses of alternate screening strategies for asymptomatic persons are needed, incorporating new data on antiretroviral therapy in pregnant and nonpregnant adults, regional variations in prevalence, targeted versus universal screening, and the costs of testing and counseling in the primary care setting.

CLINICAL INTERVENTION

Clinicians should assess risk factors for HIV infection in all patients by obtaining a careful sexual history and inquiring about drug use. Counseling and testing for HIV should be offered to all persons at increased risk for infection: those seeking treatment for sexually transmitted diseases men who have had sex with men after 1975 past or present injection drug users persons who exchange sex for money or drugs, and their sex partners women and men whose past or present sex partners were HIV-infected, bisexual, or injection drug users and persons with a history of transfusion between 1978 and 1985 ("A" recommendation).

Pregnant women in these categories, and those from communities (e.g., states, counties, or cities) where the prevalence of seropositive newborns is increased (e.g., >=0.1%) should be counseled about the potential benefit to their infant of early intervention for HIV, and offered testing as soon as the woman is known to be pregnant ("A" recommendation). Repeat testing may be indicated in the third trimester of pregnancy for women at high risk of recent exposure to HIV. There is insufficient evidence to recommend for or against universal prenatal screening for HIV in low-prevalence communities ("C" recommendation). A policy of offering screening to all pregnant women may be recommended on other grounds, including patient preference, easier implementation, and increased sensitivity compared to screening based on community prevalence and reported risk factors. Careful quality control measures and patient counseling are essential to limit the potential adverse effects from indeterminate and false-positive test results during pregnancy. Testing infants born to high-risk mothers, with permission of mother, is recommended when antibody status of mother is unknown. ("B" recommendation).

There is insufficient evidence to recommend for or against routine HIV screening in persons without identified risk factors ("C" recommendation). Recommendations to screen sexually active young women and men in high-risk communities can be made on other grounds, based on the increasing burden of heterosexual transmission and the insensitivity of screening based on self-reported risk factors. Similarly, routine HIV screening may be reasonable in groups such as prisoners, runaway youth, or homeless persons, where the prevalence of high-risk behaviors and HIV is generally high. The definition of high-risk community is imprecise. Clinicians should consult local public health authorities for advice and information on the epidemiology of HIV infection in their communities. More selective screening may be appropriate in low-risk areas. Testing should not be performed in the absence of informed consent and pretest counseling, which should includes the purpose of the test, the meaning of reactive and nonreactive results, measures to protect confidentiality, and the need to notify persons at risk. Patients who wish to be tested anonymously should be advised of appropriate testing facilities.

A positive test requires at least two reactive EIAs and confirmation with WB or IFA, performed by experienced laboratories that receive regular external proficiency testing. A separate sample should be submitted for persons found to be seropositive for the first time, to rule out possible error in specimen handling. Patients with indeterminate WB results should be evaluated individually to determine whether findings are likely to represent recent seroconversion. Repeat testing should be performed 3-6 months after indeterminate test results, or sooner if recent seroconversion is suspected. A stable indeterminate WB pattern is not indicative of HIV infection.

Seropositive patients should receive information regarding the meaning of the results, the distinctions between casual nonsexual contact and proven modes of HIV transmission, measures to reduce risk to themselves and others, symptoms requiring medical attention, and available community resources for HIV-infected persons. Clinicians should explore potential barriers to changing high-risk behavior in seropositive and seronegative individuals. Guidelines for HIV counseling have been published by the PHS. ¹⁵⁹ Seropositive persons should be evaluated for severity of immune dysfunction and screened for other infectious diseases such as tuberculosis (see Chapter 25). Guidelines for the management of early HIV infection and prevention of opportunistic infections have been published by the Agency for Health Care Policy and Research ⁶⁷ and the CDC. ^97,107,111 Arrangements for follow-up medical care are especially important for drug users, who may require assistance in gaining entrance to a drug treatment program (see Chapter 53). All seropositive individuals should be encouraged to notify sex partners, persons with whom injection needles have been shared, and others at risk of exposure. Seropositive cases should be reported confidentially or anonymously to public health officials in accordance with local regulations.

Persons with nonreactive test results should be informed that the risk of acquiring subsequent HIV infection can be prevented by maintaining monogamous sexual relationships with uninfected partners. Other measures to reduce the risk of infection (consistent use of condoms, etc.) should be specifically mentioned (see Chapter 62). The frequency of repeat testing of seronegative individuals is a matter of clinical discretion. Periodic testing is most important in patients who continue high-risk activities. In patients with recent high-risk exposure (e.g., sex with HIV-infected partner), repeat testing at 3 months may be useful to rule out initial false-negative tests.

The draft update of this chapter was prepared for the U.S. Preventive Services Task Force by David Atkins MD, MPH.

29. Screening for Chlamydial Infection Including Ocular Prophylaxis in Newborns

Infection with C. trachomatis is the most common bacterial sexually transmitted disease (STD) in the U.S., affecting an estimated 4 million persons at a cost of $2.4 billion each year. ^1,2 The medical consequences and costs of infection are greatest in women, who may develop urethritis, cervicitis, or pelvic inflammatory disease (PID i.e., salpingitis or endometritis). Chlamydial infections are responsible for 25-50% of the 2.5 million cases of PID that are reported annually in the U.S. ³ PID is an important cause of infertility and ectopic pregnancy in American women and may lead to chronic pelvic pain. Data from other countries suggest that infection with chlamydia may be a cofactor in heterosexual transmission of HIV infection. ⁴ In men, chlamydia is responsible for 30-40% of the 4-6 million visits each year for nongonococcal urethritis and half of over 150,000 cases of acute epididymitis. ¹

Up to 25% of men and 70% of women with chlamydial infection are asymptomatic. ⁵ Immunologic surveys suggest that chlamydial infection increases the risk of infertility and ectopic pregnancy even in women who never develop clinical PID, most likely because the symptoms of salpingitis may be mild or nonspecific. ¹ Asymptomatic infections in men and women also serve as an important reservoir for new infections.

Age is the strongest demographic predictor of chlamydial infection. Men and women under 25 account for the large majority of cases, ⁶ and prevalence of infection is highest among young women age 15-19. Although risk factors for chlamydia are similar to those for other STDs, chlamydia is distinct in that the prevalence of infection is substantial (>5%) among sexually active female adolescents in general, regardless of race, place of residence, or socioeconomic status. ^1,7 For example, infection was present in 5-8% of North American female college students at student health clinics ^8,9 and 8-26% of teenage girls attending adolescent clinics. ^10,11 The high risk in young women probably reflects both behavioral and physiologic factors (increased exposure of cervical columnar epithelium in young women). ¹² Other important risk factors for chlamydial infection include having multiple sex partners, a new sex partner, or an infected sex partner inconsistent use of barrier contraceptives and cervical ectopy on examination. ^1,7,13-18 Among 1,800 women ages 15-34 screened in a health maintenance organization, marital status was the single strongest predictor of infection: prevalence was less than 1% among married women, 7% among single women, and 3-4% among those divorced or living as married. ¹⁵ Chlamydial infection is more prevalent among blacks than among whites or Hispanics. ^15,19 In routine screening, women with vaginal discharge, cervicitis, or cervical friability (i.e., bleeding induced by swab) were more likely to be infected. ^7,15 Chlamydial infection is common among women with other STDs, incarcerated women, ²⁰ and women seeking abortions. ²¹ In high-risk urban communities, chlamydia was detected in 6-11% of asymptomatic, sexually active male adolescents. ^22,23

The overall prevalence of chlamydial infection among pregnant women in the U.S. is estimated to be about 5%, but it varies widely (0-37%), depending on age and other risk factors. ²⁴ Many sites serving younger women and high-risk urban communities have reported a substantially higher prevalence of infection (10-25%). ^25,26 Infection during pregnancy increases the risk of endometritis, both after delivery and after elective abortion. ^1,27 Each year more than 155,000 infants are born to chla-mydia-infected mothers, and the organism is transmitted to the fetus in over half of deliveries. ²⁴ Neonatal infection can result in ophthalmia neonatorum and pneumonia.

The most specific test for chlamydial infection in asymptomatic persons is culture. Urethral and endocervical cultures have been estimated to have a sensitivity of about 70-90% and a specificity of 100%. ^1,22 In addition to its variable sensitivity, culture is expensive, not uniformly available, requires careful handling of specimens, and takes 3-7 days for results. In one study, one fourth of women with positive cultures did not return for therapy. ²⁸ In men, screening with culture requires obtaining specimens with urethral swabs, which is unacceptable to many asymptomatic men. ²²

A variety of nonculture tests are now available, offering the advantages of easier handling and processing, lower costs, wider availability, and more timely results. Commercially available tests employ enzyme immunoassay (EIA), direct fluorescent antibody (DFA), DNA probe, polymerase chain reaction (PCR), or solid-phase colorimetric assays ²⁸ to detect chlamydia in urethral or cervical specimens. Tests using ligase chain reaction (LCR) are awaiting Food and Drug Administration (FDA) approval. ²⁹ Of these tests, EIA and DFA tests have been most widely evaluated, with reported sensitivities of 70-90% and high specificity (97-99%). ¹ False-positive EIA results may result from cross-reaction with other vaginal flora or urinary pathogens, but confirmation of positive tests using blocking antibody increases specificity to close to 100%. Studies in STD clinics indicate that DNA probe, PCR, and LCR can each be very sensitive and specific (>95%). ^30,31 Sensitivity of commercial PCR and DNA probe kits was significantly lower (60-75%) in some studies, ^32,33 however, and the performance of these assays for screening asymptomatic patients needs further evaluation. The arrival of competitively priced, commercial kits is likely to make these increasingly popular alternatives to chlamydia culture.

The ability to detect chlamydial infection in centrifuged, first-void urine specimens may make screening asymptomatic men more feasible. ^22-24 Urine dipsticks can detect leukocyte-esterase (LE) activity, an indicator of urethritis or upper urinary infections. However, the sensitivity of LE testing for chlamydial infection is variable (40-100%), ¹ and the low predictive value of LE in asymptomatic young men (11% in one study ²² ) necessitates use of confirmatory tests. Testing urine specimens with EIA is more sensitive (77-91%) and specific (97-100%), but it substantially increases the cost per confirmed case. ^22,34 PCR and LCR assays appear to have the highest sensitivity and specificity (95-99%) for chlamydia using urine specimens. ^23,29,35 A recent study reported that LCR assays of urine were also very sensitive and specific for chlamydial infection in women (94% and 99.9%, respectively). ³⁶

Even with highly specific tests, the likelihood that a positive result indicates true infection varies with the prevalence of infection in the population being screened. Assuming a sensitivity of 80% and specificity of 98%, the positive predictive value of a test will range from 82% when prevalence of chlamydia is high (10%), to only 45% when prevalence is low (2%). As a result, independent confirmation of positive results from some nonculture tests may be necessary to prevent false-positive results in low-risk patients.

In prospective studies of screening in low-risk populations, risk scores based on age, other risk factors, and findings on physical examination successfully identified a subpopulation of high-risk women (prevalence 6% or higher) who accounted for the large majority of all infections. ^15,16,37

Early detection of chlamydial infections in asymptomatic persons permits initiation of antibiotic therapy to eradicate infection. The benefits of detecting and treating asymptomatic infection in pregnancy have been demonstrated in several large cohort studies of high-risk women screened at the first prenatal visit. ^26,38 Infected women who received erythromycin had significantly lower rates of preterm delivery, rupture of membranes, and low birth weight compared to infected women who were untreated or treatment failures. In one study, treatment was associated with lower perinatal mortality among children. ²⁶ Some of the benefit may have been due to effects of erythromycin on pathogens other than Chlamydiaor underlying differences between treated and untreated women.

Eradication of asymptomatic infection is also likely to reduce the complications of chlamydial infection in nonpregnant women. Proving a benefit on long-term se-quelae of infection (e.g., infertility and ectopic pregnancy) is difficult, but a recent trial in a large health maintenance organization demonstrated that at-risk women randomized to receive routine chlamydia screening were less than half as likely to develop PID over the next year (1% vs. 2.2%). ³⁷ Hospitalizations for PID also declined in Sweden in association with increased chlamydia screening, but other changes in sexual behavior are likely to have contributed to this trend. ³⁹ Treatment effectively eradicates chlamydial infection, but it has traditionally required an extended course of medication. A 7-day course of tetracycline or doxycycline results in a short-term cure in 92-100% of women and 97-100% of men. ¹ Single-dose therapy with azithromycin is as effective as doxycycline and may be a suitable alternative when noncompliance is a concern. ⁴⁰ The benefits of early detection are limited by high rates of reinfection or treatment failure in some populations. ¹ In follow-up studies of adolescent women treated for chlamydia, 26-39% are infected 2-5 years later. ^41,42 Treatment failures are usually due to failure to treat sex partners, noncompliance with therapy, or reinfection. Referral of sex partners of cases is important, since up to one third of male partners, and a majority of female partners, are infected. ⁵

Chlamydia may cause epididymitis, but serious complications of chlamydial infection are uncommon in men. Although screening and treating high-risk young men has the potential to reduce the incidence of chlamydia, the impact of routine screening in men has not been examined prospectively, or compared to the current strategy of screening women and treating male partners. A variety of other factors will influence whether screening men will significantly reduce the incidence of new infections: duration of asymptomatic period, rates of transmission from asymptomatic men to their female partners, compliance with treatment, and rates of re-infection in young men.

Between 20% and 50% of all infants born to infected mothers develop chlamydial conjunctivitis, but there is conflicting evidence of the benefit of universal ocular prophylaxis with topical antibiotics (erythromycin, tetracycline, or silver nitrate) after birth to reduce the incidence of chlamydial ophthalmia neonatorum. ^43-45 In a recent trial in Kenya, where maternal chlamydial infection is common, povidone-iodine was significantly more effective than erythromycin or silver nitrate for preventing chlamydial conjunctivitis in newborns. ⁴⁶ The failure rate of ocular prophylaxis for chlamydia has been estimated to be 7-19%, and chlamydial ophthalmia (unlike gonococcal ophthalmia) is rarely associated with serious ocular complications. ⁴⁵ In a trial among infants born to low-risk American women, prophylaxis with silver nitrate or erythromycin reduced the incidence of conjunctivitis compared to placebo (8-9% vs. 15%) regardless of treatment, however, most cases were mild and due to organisms other than chlamydia ⁴⁷

Screening for chlamydia in asymptomatic sexually active female adolescents (under 20 years old), and in other women with risk factors for infection, is recommended by the Centers for Disease Control and Prevention (CDC), ¹ the American College of Obstetricians and Gynecologists (ACOG), ⁴⁸ the American Academy of Pediatrics (AAP), ⁴⁹ Bright Futures, ⁵⁰ the American Medical Association, ⁵¹ the American Academy of Family Physicians (AAFP), ⁵² and the Canadian Task Force for the Periodic Health Examination (CTF) ⁵³ AAFP recommendations are under review. Some of these organizations also make these recommendations for adolescent males and young men at high risk. Risk factors cited by various organizations include age under 25, new or multiple sex partners in the past 3 months, inconsistent use of barrier contraception, the presence of mucopurulent cervicitis or cervical friability, the diagnosis of other STDs, and others. An expert panel convened in 1994 by the Institute of Medicine, National Academy of Sciences, is developing recommendations for public health strategies to control STDs, including chlamydia.

The CTF recommends that all pregnant women be screened for asymptomatic chlamydial infection. ⁵³ Both ACOG and CDC recommend screening with chlamydial culture in high-risk pregnant women (including those under age 25), at the initial prenatal visit and/or in the third trimester. ^1,48 No major organization recommends routine screening of the general population. The CDC, CTF, AAP, and AAFP all recommend routine ocular antibiotic prophylaxis for all newborns, primarily to prevent ophthalmia neonatorum due to Neisseria gonorrhoeae rather than Chlamydia (see Chapter 27). ^1,45,49,52 Ocular prophylaxis is required by law in most states in the U.S.

The substantial long-term morbidity from chlamydia in women, the high prevalence of asymptomatic infection, and the availability of reliable screening tests and effective treatments all suggest that screening for asymptomatic chlamydial infection may be a useful strategy. There is now preliminary evidence from one trial that screening high-risk asymptomatic, nonpregnant women can reduce the incidence of PID. Screening and treatment of infected women and their partners is also likely to reduce the incidence of new infections, although conclusive proof of this is not available. While high-risk sexual behavior is an important determinant of risk of chlamydial infection, the generally high prevalence of chlamydia among sexually active female adolescents supports routine screening in this population. ⁷

The optimal criteria for screening other women depend on the local burden of disease and resources available for screening. Risk of infection depends on both individual sexual behavior and the prevalence of chla-mydia in the community. Where the prevalence of infection is documented to be low (<5%), targeting screening to women with multiple risk factors for infection may be most efficient. Because self-reported sexual history is often an unreliable indicator of risk, however, broader screening of young women may be preferable in practices or communities where chlamydia is highly prevalent.

There is fair evidence that treatment of chlamydial infection during pregnancy is associated with improved outcomes for both infants and mothers. Due to the low prevalence of infection in women who are older or married, universal screening is not indicated in pregnancy. Since the primary benefit of treatment in pregnancy is to prevent perinatal and postpartum complications, screening high-risk women in the third trimester is likely to be effective and reduce the opportunity for reinfection prior to delivery. Although ocular prophylaxis appears to reduce the risk of chla-mydial ophthalmia neonatorum, screening and treating high-risk mothers may be a more effective means of preventing chlamydial infections in newborn infants.

Screening is less likely to benefit asymptomatic men, but screening young men using urine-based tests (LE, EIA, or PCR) may be a useful strategy to prevent spread of infection in communities where chlamydia is common. Whether routine screening in men is effective in reducing the incidence of chlamydial infection deserves further study, however.

Nonculture methods are appropriate alternatives to cell culture for diagnosis of infection. The choice of optimal testing strategy will depend on available resources, the prevalence of chlamydia, and the potential adverse consequences of false-positive diagnoses. Newer methods such as PCR or LCR are likely to offer advantages due to improved sensitivity and specificity further evaluations of new commercial test kits are needed in asymptomatic populations before specific recommendations can be made.

Cost-effectiveness analyses have concluded that screening for chlamydia with nonculture tests is cost-effective during routine gynecologic visits ^54-56 and during pregnancy ⁵⁷ when prevalence of infection exceeds 6-8%. Others have suggested that screening is cost-effective at even lower prevalence. ¹³ Screening asymptomatic adolescent males with urine-based tests was calculated to be cost-saving, primarily by reducing infections in female partners, but has not been compared to the current strategy of screening women. ³⁴

CLINICAL INTERVENTION

Routine screening for asymptomatic infection with Chlamydia trachomatis during pelvic examination is recommended for all sexually active female adolescents and for other women at high risk for chlamydial infection ("B" recommendation). Patient characteristics associated with a higher prevalence of infection include: history of prior STD, new or multiple sex partners, age under 25, inconsistent use of barrier contraceptives, cervical ectopy, and being unmarried. Actual risk will depend on number of risk factors and local epidemiology of chlamydial infection. Clinicians may wish to consult local public health authorities for guidance in identifying high-risk populations within their community. Algorithms to identify high-risk women have been published. ^15,16 In clinical settings where the prevalence of infection is known to be high (e.g., some urban family planning clinics), routine screening of all women is appropriate. Clinicians should remain alert for findings suggestive of chlamydial infection (e.g., mucopurulent discharge, cervical erythema, or cervical friability) during pelvic examination of asymptomatic women.

Pregnant women at high risk of infection (including age under 25) should be tested for chlamydia ("B" recommendation). The optimal timing of screening in pregnancy is uncertain. There is insufficient evidence to recommend for or against screening all women during pregnancy ("C" recommendation).

There is insufficient evidence to recommend for or against routine screening in high-risk men ("C" recommendation). In clinical settings where asymptomatic infection is highly prevalent in men (e.g., urban adolescent clinics), screening sexually active young men may be recommended on other grounds, including the potential to prevent transmission to uninfected sex partners. Routine screening for chlamydia is not recommended in the general population of low-risk adults ("D" recommendation).

In women, endocervical specimens should be obtained for cell culture or nonculture assays. Verification of positive nonculture results may be necessary, depending on the underlying risk in the patient and potential adverse consequences of a false-positive result. The choice of screening test for asymptomatic men is left to clinical discretion. Urine LE dipstick is much less expensive than urine assays using EIA, PCR, or LCR, but it is also less sensitive and specific for asymptomatic chlamydial infection. The optimal frequency of testing has not been determined for women or men and is left to clinical discretion.

Routine ocular antibiotic prophylaxis with silver nitrate, erythromycin, or tetracycline is recommended for all newborn infants to prevent ophthalmia neonatorum due to gonorrhea and is required by law in most states (see Chapter 27). There is insufficient evidence to recommend for or against universal ocular prophylaxis of newborns solely for the prevention of chlamydial conjunctivitis ("C" recommendation).

The draft update of this chapter was prepared for the U.S. Preventive Services Task Force by David Atkins, MD, MPH, based in part on background materials prepared by H. Oladele Davies, MD, MSc, FRCPC, and Richard B. Goldbloom, MD, FRCPC, for the Canadian Task Force on the Periodic Health Examination.

Primary genital herpes simplex virus (HSV) infection occurs in approximately 200,000-500,000 Americans each year, ¹ mostly in adolescents and young adults. Between 25 and 31 million individuals are chronically infected. ^1,2 Both HSV types 1 (HSV-1) and 2 (HSV-2) can infect the genitalia, but HSV-2 causes the majority of primary and recurrent genital herpes infections. ³ Most HSV-2 infections are asymptomatic, detected only by seroconversion ^4,5 16% of the adult population is HSV-2 seropositive. ² In symptomatic genital herpes, the chief clinical morbidity is painful, pruritic vesicles that may coalesce into large ulcerative lesions. ³ Systemic symptoms, such as fever, headache, myalgia, and malaise, are reported by two thirds of patients with primary first-episode genital herpes, and serious complications such as meningitis (reported in 8%) may ensue. ³ After initial infection, the virus enters a latent state in spinal cord ganglia. Infected persons may periodically experience viral reactivations that can be asymptomatic, characterized by viral shedding alone, or symptomatic, marked by a recurrence of signs and symptoms that are less severe than those of primary genital herpes. ³ The sexual contacts of individuals with either symptomatic or asymptomatic disease are at risk of becoming infected. ⁶

In pregnant women, the rate of genital herpes reported as a maternal risk factor on birth certificates is 8.0/1,000 live births. ⁷ Pregnant women with genital HSV infection can transmit the virus to their newborns. The majority (82-87%) of neonatal infections occur during delivery, but some also occur in utero or postnatally. ^8-10 In 1984 it was estimated that the minimum annual incidence of neonatal HSV infections in the United States, based on voluntary reporting, was 4/100,000 live births ¹¹ intensive local surveillance in one county in Washington found a rate of 12/100,000 live births. ¹² One fourth of HSV-infected neonates develop disseminated disease and one third have encephalitis. ^13,14 Even with antiviral treatment, the mortality rate is 57% among infants with disseminated disease and 15% among those with encephalitis. ¹³ Severe neurologic impairment occurs in about one third of those who survive encephalitis or disseminated disease. ^13,14 Among infants with infection apparently limited to mucocutaneous involvement, death or severe impairment is rare but other complications such as visual impairment or seizures occur in about 5%. ^13,14

History and physical examination are not adequate screening tests for either active (i.e., transmissible) or latent genital HSV infection, because most infected persons are asymptomatic ^4,5,15 their clinical manifestations may resemble a number of other causes of genital ulcerations ¹⁶ and viral shedding in association with recurrent disease may be asymptomatic. ^3,17

The most commonly used test for detecting active genital HSV infection is viral culture. The sensitivity of this test is variable, however, depending upon the viral titer present, ranging in one study from 93% for vesicles to 72% for ulcers and 27% for crusted lesions, and from 82% for ulcerative lesions in first episodes to 43% for ulcerative lesions in recurrent episodes. ^16,18 Since the viral titer in asymptomatic shedding is 10-100 times less than that in symptomatic episodes, ¹⁷ the sensitivity of viral culture for detecting HSV infection in asymptomatic individuals is likely to be low. In addition, conventional viral culture is time-consuming and technically demanding, and only 40-48% of positive results are available within 24 hours. ^19-21 Viral culture techniques may be modified to produce final test results within 16-24 hours, but sensitivity is then reduced by 5-20% compared with final conventional culture results in symptomatic patients ^20-24 sensitivity is likely to be reduced further in asymptomatic patients.

Other rapid screening methods, such as cytology and direct fluorescent antibody staining, are widely available but are substantially less sensitive than is conventional viral culture. ⁶ Newer methods, not yet licensed for clinical diagnostic testing for HSV, include enzyme immunoassay (EIA), polymerase chain reaction (PCR), and DNA hybridization. EIA and PCR show concordance of >93% with the results of conventional viral culture in symptomatic women. ^25-28 In one study in asymptomatic pregnant women, PCR had a reported concordance of 100% with conventional culture. ²⁷ EIA, however, had a concordance of only 59% with conventional viral culture in a large study of samples taken primarily from "presumed asymptomatic" pregnant women. ²⁵ EIA can provide results within several hours, whereas even with automated techniques PCR currently requires more than a day to process and is extremely labor intensive. Both EIA and PCR may react with nonviable virus or viral particles, ^25-28 thus overestimating the risk of infectivity. Results from studies of DNA hybridization appear less promising, with a sensitivity of 25% and specificity of 88% compared to conventional culture, ²² and 43% and 71%, respectively, compared to cytology, ²⁹ on samples from symptomatic patients.

An estimated 35-80% of infants with neonatal herpes are born to women with no known history of genital herpes or physical signs of infection at delivery. ^10,12,13 Therefore, screening asymptomatic pregnant women has the potential of identifying unrecognized active HSV infections. In order for routine screening at the onset of labor to be useful for clinical decision making regarding surgical or medical intervention to prevent neonatal herpes, rapid and accurate methods of detecting asymptomatic HSV infections likely to be transmitted would be needed. The yield of routine screening by viral culture in asymptomatic pregnant women is quite low large-scale screening studies have isolated HSV by culture from only 0.20-0.35% at the time of delivery. ^30-32 A positive viral culture does not necessarily mean an infant will become infected during delivery. The risk of acquiring neonatal herpes infection from an asymptomatic pregnant woman with active viral shedding from reactivated disease is less than 5%, whereas from a woman with first-episode genital disease the risk is 33%. ³¹ A negative culture, however, does not eliminate an infant's risk of infection. In one large cohort study, the mothers of 30% (3 of 10) of the infected newborns were culture negative at the time of delivery, ³¹ and in a case series of infants with neonatal herpes, 61% (54 of 89) of the pregnant women had negative cultures within the 2 weeks before delivery. ³³ In asymptomatic women with a history of recurrent herpes, surveillance cultures during the 4 weeks before delivery did not correlate with viral shedding at delivery. ³⁴ Thus, screening near term is not adequate to predict accurately the likelihood of HSV transmission from asymptomatic pregnant women to their offspring.

Antibody testing can accurately distinguish HSV-seropositive from HSV-seronegative persons and therefore may be useful to detect asymptomatic carriers at potential risk for transmitting disease, as well as persons susceptible to primary infection. Commercial assays are insensitive to recent infections, however, and they are unreliable for distinguishing HSV-2 from HSV-1 antibodies. ^35,36 Antibody test results do not indicate whether the virus is currently capable of being transmitted.

The detection of HSV infection in asymptomatic, nonpregnant individuals would be useful if treatment were available to either eradicate latent HSV infection or to prevent transmission to sex partners by eliminating or reducing viral shedding. There is currently no effective treatment for eradicating latent herpes infection. Both episodic and continuous oral acyclovir reduce viral shedding, lesion healing time, and local and systemic symptoms during symptomatic primary first-episode and recurrent genital HSV infections. ^37-42 When used continuously for up to 4 years, oral acyclovir produces only minor side effects and minimal emergence of resistant strains in immunologically normal individuals. ^41-43 The beneficial effects of acyclovir on lesion healing and viral shedding in symptomatic individuals have not been documented to prevent or reduce transmission to sex partners, however. Based on a single, small before-after study, oral acyclovir does not appear to prevent asymptomatic viral shedding, ⁴⁴ and no studies have evaluated its ability to decrease infectivity and disease transmission during episodes of asymptomatic shedding.

Routine screening for HSV-2 antibodies may be useful to identify persons with previously unrecognized infection, ⁴ who could then be instructed in the recognition of recurrent episodes. Such instruction results in recognition of clinically symptomatic genital herpes on follow-up in 50% of seropositive persons with previously unrecognized infection. ⁴⁵ Counseling seropositive persons to avoid sexual activity or to use condoms during symptomatic episodes may reduce transmission of herpes to their sex partners. ^45,46 Among a series of 144 couples with one partner with recurrent herpes and one without antibody, all of whom were advised to abstain from skin-to-skin contact during active episodes and about the risks of transmission during asymptomatic periods, acquisition of genital herpes occurred in 6% who used barrier contraception and 14% who did not (p = 0.19), but only 15% of couples used condoms routinely. ⁴⁷ Although not specifically designed to evaluate counseling, this study suggests a limited benefit from knowledge of susceptibility. The effectiveness of this strategy in preventing HSV-2 transmission has not been evaluated adequately it may not provide any incremental benefit over routine counseling of all sexually active adults regarding prevention of sexually transmitted diseases. ⁴⁸

The early detection of active HSV infection may be of greater importance during pregnancy because cesarean delivery can be performed. This has the potential to reduce the exposure of the neonate to virus in the birth canal that occurs during vaginal delivery, although the evidence for the effectiveness of this intervention is limited. Small, uncontrolled case series of symptomatic women with positive genital cultures during the 1-2 weeks before delivery ^49,50 or with positive cervical cultures at the time of delivery ⁵¹ suggest a protective effect of cesarean deliveries no controlled trials have evaluated this intervention. None of these studies differentiated primary from recurrent infections, which have different rates of HSV transmission. Cesarean delivery is clearly not completely effective, since large case series of newborns infected with HSV reveal that 19-33% of them were delivered by cesarean delivery. ^11,33,52 Information concerning the effectiveness of cesarean delivery in preventing neonatal herpes transmission by asymptomatic pregnant women comes from a large cohort study that screened such women by viral culture during early labor. ³¹ In this study, 8% (1 of 13) of infants delivered by cesarean delivery to culture-positive women became infected, compared to 14% (6 of 43) of infants delivered vaginally to culture-positive women. Drawing conclusions from this study is difficult, however, because sample size was insufficient to establish statistical significance reasons for selection of vaginal delivery are not given and differences between the two groups in the proportions of primary versus recurrent infections, site of positive culture (i.e., cervical vs. other), and duration of rupture of membranes are not delineated. Thus, the benefit of cesarean delivery in either symptomatic or asymptomatic culture-positive women is not established.

Even if cesarean delivery does offer some benefit in preventing the transmission of HSV to newborns, more definitive studies would be needed to determine the proper indications for abdominal delivery. For example, it is not clear whether cesarean delivery would be indicated when the risk of herpes transmission is low, e.g., in the setting of asymptomatic viral shedding, recurrent symptomatic disease, or when labial but not cervical cultures are positive. ^31,34,51,53 In these relatively low-risk situations, the potential benefit to the fetus of averting HSV infection may not outweigh the known risk of complications in the mother and infant due to cesarean delivery. In cohort studies, cesarean delivery has been associated with increases in both maternal morbidity and mortality compared to vaginal delivery, ^54-56 even when stratified by maternal diagnosis. A 1993 decision analysis model calculated that cesarean delivery for herpes lesions at delivery in women with recurrent genital HSV leads to 1,580 excess (i.e., performed solely to prevent HSV transmission) cesarean deliveries for every neonate saved from death or neurologic sequelae, and 0.57 maternal deaths for every neonatal death prevented total costs were $2.5 million per case of HSV averted, and $203,000 per quality adjusted life-year (QALY) gained. ⁵⁷ These estimates are sensitive to risk of vertical transmission (estimated to be 1%) and to the efficacy of cesarean delivery (estimated to be 80%) reductions in either of these could result in maternal deaths exceeding neonatal mortality. The decision analysis results change dramatically if only women with primary HSV infections are entered. In women with herpes lesions at delivery but no previous history of genital HSV, nine excess cesarean deliveries would be performed for every neonate saved, with 0.004 maternal deaths per neonatal death prevented, at a total savings of more than $38,000, saving $2600 per QALY gained. Net benefits persisted across all likely ranges of values entered into the model.

Serologic screening may prove useful for the prevention of primary HSV-2 infections in pregnancy. One study screened pregnant women and their partners for type-specific antibodies to herpes, and found that 10% (18 of 190) of the women were seronegative with seropositive partners, and therefore were at risk of contracting a primary HSV-2 infection during pregnancy 7 of 18 couples continued to have unprotected intercourse after being informed of their serologic status, and 1 of the 7 seroconverted during pregnancy. ⁵ Studies evaluating the effectiveness of counseling such couples to abstain from sexual intercourse or to use condoms regularly during pregnancy to prevent neonatal herpes transmission have not been performed.

Another potential strategy for preventing the transmission of HSV to newborns is offering prophylactic acyclovir to pregnant women with recurrent herpes. A case series of 15 pregnant women with recurrent genital herpes demonstrated that suppressive treatment with acyclovir after 38 weeks of gestation was well tolerated with no toxicity to the mothers or infants. ⁵⁸ None of the women experienced new symptomatic recurrences or asymptomatic viral shedding after beginning treatment and none of their infants developed neonatal infection. In a pilot randomized controlled trial, women with recurrent herpes who received acyclovir continuously at least 1 week before expected term had significantly fewer HSV recurrences/positive cultures and a significantly lower rate of cesarean delivery for herpes. ⁵⁹ Four randomized controlled studies are currently being conducted, in the United States, Norway, and England, to determine the effectiveness and safety of prophylactic acyclovir in reducing the risks of asymptomatic shedding, cesarean delivery, and neonatal transmission when given in late pregnancy to women with histories of recurrent herpes (H. Watts, personal communication, July 1995 L. Scott, personal communication, July 1995). ^60,61 Although acyclovir has not been found to be teratogenic in standard animal testing, and no recognizable pattern of birth defects has been detected among 601 reported cases of exposure during pregnancy, current data are only sufficient to exclude a teratogenic risk of at least 2-fold over the 3% baseline risk of birth defects. ^62,63

The American College of Obstetricians and Gynecologists, ⁶⁴ the American Academy of Pediatrics, ⁶⁵ the Canadian Task Force on the Periodic Health Examination, ⁶⁶ and the Infectious Disease Society of America ⁶⁷ recommend against surveillance cultures for herpes infections in asymptomatic pregnant women. All four groups suggest careful examination of all women at the time of delivery and culture of active lesions, with cesarean delivery for women with positive findings on clinical examination. ^64-67 No organizations currently recommend screening for genital herpes simplex virus or antibody in the asymptomatic general population.

There are currently no commercially available tests that are adequate to detect latent HSV-2 infections in asymptomatic patients. Even if accurate type-specific serology becomes widely available, there is no proven treatment to eradicate latent infection or to eliminate viral shedding in order to prevent disease transmission. Similarly, there is limited evidence that counseling persons known to have HSV offers any benefit over routine counseling of all sexually active adults to prevent sexually transmitted diseases. Evidence does not therefore support screening the asymptomatic general population for HSV infection.

For pregnant women (and those planning conception), the potential benefit of detecting asymptomatic and unrecognized HSV infection is the prevention of neonatal HSV transmission. The risk of transmitting HSV to their infants is slightly increased in pregnant women with asymptomatic shedding of HSV due to reactivated disease at delivery, and it is substantially increased in women with primary HSV infection at delivery. Culture results at the onset of labor are rarely available in time to affect clinical decision making, and there is good evidence that positive viral cultures in the weeks prior to delivery do not accurately predict the risk of neonatal HSV transmission. More rapid tests that could be performed at the onset of labor are either substantially less sensitive than culture or not yet widely available. Women with primary first-episode HSV infection at delivery are more likely to present with symptoms and signs detectable by physical examination, but such examinations have not been shown to be sensitive or specific. Even if the diagnosis of HSV is made by physical examination during labor, the evidence supporting the effectiveness of cesarean delivery in preventing neonatal HSV transmission is of poor quality, while there is fair evidence that cesarean delivery increases risk to the mother and fetus compared to vaginal delivery. A recent decision analysis predicts that if cesarean delivery prevents 85% of neonatal HSV infections that occur following vaginal delivery, a physical examination at labor for symptoms or signs of genital herpes would minimize the ratio of excess cesarean deliveries to cases of neonatal HSV infection averted, compared to other screening methods or no screening. ⁶⁸ Another model that evaluated performing a physical examination at delivery, followed by cesarean delivery for women with genital herpes lesions, found clear evidence of benefit only for women with no history of genital herpes. ⁵⁷ For women with recurrent herpes, the risk to the mother may outweigh that to the neonate, depending on assumptions made about the efficacy of cesarean delivery and the likely HSV transmission rate. The use of acyclovir in pregnancy to reduce neonatal HSV has not been adequately evaluated, but trials are ongoing.

Although a history of genital herpes does not accurately predict HSV seropositivity, if the pregnant woman who lacks such a history has a partner known to have genital herpes, counseling to prevent HSV transmission to the woman could prevent primary HSV infection, thereby preventing neonatal HSV at little cost or risk to the patient. When commercially available, HSV serotyping at the first prenatal visit with serotesting of the partners of those who are HSV-2 seronegative would allow more accurate detection of pregnant women at risk for primary HSV infection. The effectiveness of counseling such women regarding primary prevention has not been demonstrated, however.

CLINICAL INTERVENTION

Routine screening for genital herpes simplex in asymptomatic persons, using culture, serology, or other tests, is not recommended ("D" recommendation). See Chapter 62 for recommendations on counseling to prevent sexually transmitted diseases.

Routine screening for genital herpes simplex infection in asymptomatic pregnant women, by surveillance cultures or serology, is also not recommended ("D" recommendation). Clinicians should take a complete sexual history on all adolescent and adult patients (see Chapter 62).

As part of the sexual history, clinicians should consider asking all pregnant women at the first prenatal visit whether they or their sex partner(s) have had genital herpetic lesions. There is insufficient evidence to recommend for or against routine counseling of women who have no history of genital herpes, but whose partners do have a positive history, to use condoms or abstain from intercourse during pregnancy ("C" recommendation) such counseling may be recommended, however, on other grounds, such as the lack of health risk and potential benefits of such behavior.

There is also insufficient evidence to recommend for or against the examination of all pregnant women for signs of active genital HSV lesions during labor and the performance of cesarean delivery on those with lesions ("C" recommendation) recommendations to do so may be made on other grounds, such as the results of decision analyses and expert opinion. There is not yet sufficient evidence to recommend for or against routine use of systemic acyclovir in pregnant women with recurrent herpes to prevent reactivations near term ("C" recommendation).

The draft update of this chapter was prepared for the U.S. Preventive Services Task Force by Paul Denning, MD, MPH, and Carolyn DiGuiseppi, MD, MPH.

Asymptomatic bacteriuria is defined as a significant bacterial count (usually >=10⁵ or 10⁶ organisms/mL) present in the urine of a person without symptoms. Asymptomatic bacteriuria may precede symptomatic urinary tract infection, characterized by dysuria, frequency, pain, fever, etc., which accounts for over 6 million outpatient visits each year. ¹ Urinary tract infection may be associated with renal insufficiency and increased mortality in adults, but these complications rarely occur among those without underlying structural and functional diseases of the urinary tract. ² In both institutionalized and noninstitutionalized elderly, urinary tract infection is the most common cause of bacteremia, which may be associated with a 10-30% case fatality rate. ^3,4 Most such bacteremia occurs in residents with indwelling catheters or urinary tract abnormalities, however. Similarly, most of the 300,000 hospitalizations each year for urinary tract infections ¹ involve patients with indwelling urethral catheters.

In children, asymptomatic bacteriuria may be a sign of underlying urinary tract abnormalities. About 10-35% of infants and children with asymptomatic bacteriuria have vesicoureteral reflux and 6-37% have renal scarring or other abnormalities (the lower prevalences generally reflecting more stringent definitions of abnormality), ^2,5-8 whereas such abnormalities are uncommon in the general population of children. ^2,9 Children with major structural abnormalities, chronic pyelonephritis, or severe vesicoureteral reflux are at increased risk of renal scarring, obstructive renal atrophy, hypertension, and renal insufficiency. ² Pyelonephritis, reflux nephropathy, and urinary tract malformations may cause as much as one fifth of cases of renal failure in children. ¹⁰ In pregnancy, 13-27% of untreated women with asymptomatic bacteriuria develop pyelonephritis, usually requiring hospitalization for treatment. ^11-14 Bacteriuria in pregnant women increases the risk for preterm delivery and low birth weight about 1.5-2-fold, and may also increase the risk of fetal and perinatal mortality. ^15-23

The risk of acquiring bacteriuria varies with age and sex. Asymptomatic bacteriuria in term infants is more common in males (estimated prevalence of 2.0-2.9% vs. 0.0-1.0% in females), but it is considerably more common in girls after age 1 (0.7-2.7% in girls vs. 0.0-0.4% in boys). ^2,5-8,24 Approximately 5-6% of girls have at least one episode of bacteriuria between first grade and their graduation from high school, and as many as 80% of these children experience recurrent infections. ² Asymptomatic bacteriuria in adulthood is more prevalent in women than men (3-5% vs. <1% in those under 60 years), and its prevalence increases with age. ^25-27 Asymptomatic bacteriuria is a common finding in older persons, especially those who are very old (20% of women and 10% of men >80 years old living in the community) or institutionalized (30-50% of women and 20-30% of men). ^3,4 Bacteriuria occurs in 2-7% of pregnant women of those who are not bacteriuric at initial screening, 1-2% will develop bacteriuria later in the pregnancy. ^28-30 An increased prevalence of asymptomatic bacteriuria (about 10-20%) has been reported in asymptomatic diabetic women, although several studies have found no increase when compared to matched nondiabetic controls or to expected age- and sex-specific population rates. ^2,31-34

The most accurate test for bacteriuria is urine culture, but laboratory charges make this test expensive for routine screening in populations that have a low prevalence of asymptomatic bacteriuria. The most commonly used tests for detecting bacteriuria in asymptomatic persons are dipstick urinalysis and direct microscopy. The dipstick test is rapid, inexpensive, and requires little technical expertise. The dipstick leukocyte esterase (LE) test, which detects esterases released from degraded white blood cells, is an indirect test for bacteriuria. When compared with culture (at least 100,000 organisms/mL), it has a sensitivity of 72-97% and a specificity of 64-82%. ^35-40 The nitrite reduction test, which detects nitrites produced by urinary bacteria (usually limited to Gram-negative bacteria), has variable sensitivity (35-85%) but good specificity (92-100%). ^35-39,41-49 In children, dipstick testing for LE and/or nitrites has been found to have sensitivity and specificity of around 80% compared to quantitative culture. ^50-57 Among pregnant women, a sensitivity of only 50% for dipstick testing compared to culture has been reported. ³⁰ False-positive and false-negative urinalysis results are due to a variety of factors, including specimen contamination, certain organisms, and the timing of specimen collection. The sensitivity of this test can be improved by obtaining first-morning specimens, preferably on consecutive days, instead of performing random collection. ⁴¹ Many of the studies assessing the accuracy of dipstick testing in children and adults do not describe the patients included. A proportion of these patients were undoubtedly symptomatic, possibly leading to bias in the accuracy estimates. In one study, dipstick sensitivity was significantly lower (56% vs. 92%) and specificity significantly higher (78% vs. 42%) in patients with few symptoms and a low prior probability of bacteriuria, compared to patients with a high prior probability of bacteriuria (i.e., those with dysuria, frequency, etc.). ⁵⁸

Examination of the sediment by microscopic urinalysis to detect bacteria and white blood cells has also been evaluated as a screening test for bacteriuria. In children (including symptomatic patients), microscopy performs similarly to dipstick testing for detection of bacteriuria. ⁵⁰ In pregnant women, microscopic analysis, with either bacteriuria or pyuria indicating a positive test, had a sensitivity of 83% but a specificity of only 59%. ³⁰ In hospitalized adults, only 3% of urine specimens that were macroscopically (including dipstick) negative had clinically significant abnormalities detected by routine microscopic examination. ^59,60 Microscopy has limited value as a screening test for asymptomatic persons because of the cost, time, and technique required. ³⁰

In populations with a low prevalence of urinary tract disorders, most positive screening tests are falsely positive. Thus, in asymptomatic men, and in asymptomatic women under age 60, a dipstick test has a positive predictive value for significant bacteriuria of less than 10% (assuming a sensitivity of 85% and a specificity of 70%). ^20,25,43 In children, the likelihood of bacteriuria in the presence of a positive dipstick screening test has been estimated at 0.1% for boys and 4% for girls. ⁵⁷ In groups at increased risk for urinary tract infection, the positive predictive value of dipstick tests is higher: 13% in pregnant women, 18% in women over age 60, 33% in diabetic women, and 44% in institutionalized older persons. ^{20,25,29,32,41,43,61-64} The predictive value of bacteriuria found on microscopic urinalysis among pregnant women was 4.2-4.5%. ³⁰

Urine screening tests are generally performed on a clean-catch specimen. In infants and young children, collection of a "clean" urine specimen is difficult, and as a result few studies of the accuracy of screening tests have included infants. Adhesive polyethylene bag specimens are the most acceptable choice, but these may have a significant contamination rate (false positives). Compared to suprapubic aspiration, positive results on bag specimens indicate true bacteriuria in only 7.5% of specimens. ⁶⁵ The collection of confirmatory sterile culture specimens by suprapubic aspiration or urethral catheterization is too invasive and costly to be considered in a screening protocol for asymptomatic infants, as is routine screening by urethral catheterization.

The early detection of asymptomatic bacteriuria may reduce the rate of bacteriuria and prevent symptomatic infection and its complications. Some observational studies suggest that persons with untreated asymptomatic bacteriuria are at increased risk of developing symptomatic urinary tract infection ^66,67 and other complications (e.g., structural damage, renal insufficiency, hypertension, or mortality). ^{41,61-64,68-71} Evidence is not conclusive, however, that these clinical outcomes are caused by bacteriuria (especially in the absence of a structural abnormality), or that early treatment results in important clinical benefits. A randomized placebo-controlled trial of conventional treatment for asymptomatic bacteriuria in both young and middle-aged women (ages 20-65) reported no significant differences in the prevalence of bacteriuria or incidence of symptomatic urinary tract infection at 1-year follow-up. ⁶⁶ Another randomized controlled trial (available only in abstract form) among women ages 16-69 years with asymptomatic bacteriuria reported significant reductions in bacteriuria at 1 and 3 years with vigorous individualized antimicrobial therapy, but did not report on clinical outcomes. ⁷² Among a cohort of middle-aged women (38-60 years) screened for asymptomatic bacteriuria, the prevalence of asymptomatic bacteriuria at 6-year follow-up in women identified with asymptomatic bacteriuria and appropriately treated remained significantly higher than in the nonbacteriuric group (23% vs. 5%) and 58% of the treated women had recurrent or persistent infection within 2 years of treatment. ²⁵ Studies evaluating the treatment or natural history of asymptomatic bacteriuria are not available for young or middle-aged men .

Randomized controlled trials in institutionalized elderly women ⁷³ and men ⁷⁴ found no decreases in genitourinary morbidity with treatment of asymptomatic bacteriuria despite a reduced prevalence of bacteriuria. In both studies, life-table analyses suggested a survival advantage for the untreated group, but the differences were not statistically significant. In women, treatment was associated with an increased incidence of adverse antimicrobial drug effects and increased reinfections. ⁷³

Among noninstitutionalized ambulatory elderly women, a randomized controlled trial reported that treatment significantly reduced the prevalence of bacteriuria at 6-month follow-up. ⁶⁷ Symptomatic urinary tract infection and mortality rates were 16.4% and 4.9%, respectively, without treatment, compared to 7.9% and 3.2%, respectively, with treatment, but these differences were not statistically significant sample size may have been inadequate to detect a difference, however. In a nonrandomized controlled trial in noninstitutionalized elderly women, treatment of asymptomatic bacteriuria did not significantly reduce mortality (adjusted relative risk 0.92, 95% confidence interval, 0.57 to 1.57), although wide confidence intervals do not exclude the possibility of a substantial benefit. ⁷⁵ A large cohort study from the same center reported no association between asymptomatic bacteriuria and mortality in ambulatory elderly women after control for confounding, even though the cure rate with treatment was 83% compared to a 16% spontaneous remission rate in untreated patients. ⁷⁵ It is not clear whether the possible but unproven benefits from treatment of such women justify routine screening or the potential adverse effects of antibiotic therapy, including drug toxicity and the development of resistant organisms while treating recurrent infections. No controlled trials of therapy for asymptomatic bacteriuria in noninstitutionalized elderly men have been reported. In a prospective cohort study of 234 elderly men followed for up to 4.5 years, 29 (12%) had asymptomatic bacteriuria at initial screening, and 20 (8%) became positive in follow-up. ⁷⁶ Of untreated bacteriuric subjects, 76% spontaneously cleared. Only five bacteriuric subjects were treated for symptomatic infection, with prompt recurrence of asymptomatic bacteriuria in three no adverse outcomes from symptomatic infection were reported. Cohort and cross-sectional studies that have included elderly ambulatory men have reported no differences in mortality, chronic genitourinary symptoms, or systemic symptoms such as anorexia, fatigue, or malaise between those with and without asymptomatic bacteriuria, after adequate adjustment for confounding variables. ^77-79

Although some trials of elderly patients may have included persons with diabetes, we found no controlled clinical trials specifically evaluating the effectiveness of early detection of asymptomatic bacteriuria in diabetics for improving clinical outcome. Case series suggest treatment of asymptomatic bacteriuria usually clears bacteriuria and may reduce clinical symptoms, but bacteriuria recurs in more than two thirds of treated patients. ^80-83 Continuous suppressive antibiotic therapy in diabetic patients can prevent re-infection but provides no posttreatment benefit. ^80,81 The long-term consequences of asymptomatic bacteriuria in this population are undefined, although in one series persistent bacteriuria did not appear to contribute to renal damage. ⁸³

The early detection of asymptomatic bacteriuria is of greater potential value for pregnant women, in whom bacteriuria is an established risk factor for serious complications, including acute pyelonephritis, preterm delivery, and low birth weight. Randomized controlled trials, cohort studies, and a meta-analysis of 8 randomized clinical trials have shown that treatment of asymptomatic bacteriuria during pregnancy can significantly reduce the incidence of symptomatic urinary tract infection, low birth weight, and preterm delivery. ^{12-14,18,20,28,84} There is little evidence regarding the optimal periodicity of screening in pregnancy. A urine culture obtained at 12-16 weeks of pregnancy will identify 80% of women who will ultimately have asymptomatic bacteriuria in pregnancy, ⁸⁵ with an additional 1-2% identified by repeated monthly screening.

In children, detection of bacteriuria might lead to the identification of correctable abnormalities of the urinary tract and the prevention of renal scarring, obstructive atrophy, hypertension, and renal insufficiency. However, in three randomized controlled trials in girls aged 5-15 years, treatment of asymptomatic bacteriuria did not significantly reduce emergence of symptoms, pyelonephritis, renal scarring, or persistence of vesicoureteral reflux. ^86-88 In two of these trials, ^86,87 sample sizes may have been too small to detect important differences, but adverse outcomes were rare in both groups. Treated and control subjects had similar growth, blood pressure, renal growth, and concentrating capacity at the end of follow-up, ranging from 12 to 48 months. In longitudinal studies from the Oxford-Cardiff Cohort screening program, girls with asymptomatic bacteriuria in childhood had an increased prevalence of asymptomatic bacteriuria in pregnancy, and among those with asymptomatic bacteriuria and renal scarring, increased preeclampsia, hypertension, and obstetric interventions. ^89,90 On the other hand, in pregnant women with a history of symptomatic urinary tract infection in childhood, there were no differences in preeclampsia or operative delivery, although asymptomatic bacteriuria was again more common. ⁹¹ All pregnancies in these studies had satisfactory maternal and fetal outcomes.

Most of the complications from urinary tract abnormalities are thought to occur before children reach school age, ² and therefore screening might be more effective in younger children. There have been no studies, however, proving that preschool urinalyses result in lower morbidity from recurrent infection or in less renal damage. ^2,92 Several studies have evaluated the natural history of asymptomatic bacteriuria detected in infancy and followed through the preschool years. In a Swedish cohort of 3,581 screened newborns, 50 infants were identified with asymptomatic bacteriuria, of whom 3 (<0.1%) were treated for underlying renal or urologic abnormalities and 2 were treated for pyelonephritis that occurred within 2 weeks of testing. ^8,93 All 45 infants with untreated asymptomatic bacteriuria followed for up to 7 years cleared either spontaneously (80%) or after antibiotic treatment for other conditions (20%). Three subsequently developed cystitis and 20% had recurrences of asymptomatic bacteriuria, but none had major renal or urologic abnormalities as measured by concentrating capacity and urography at a median follow-up of 32 months. Forty infants developed symptomatic urinary tract infection in the first year of age, but only 2 (5%) had evidence of bacteriuria on previous screening. In another cohort of 1,617 healthy infants followed for 5 years, screening for asymptomatic bacteriuria detected 5 cases (0.3%) with high-risk lesions (such as obstructive uropathy, vesicoureteral junction ectopia, etc). ⁹⁴ Whether early detection of bacteriuria improved prognosis was not established by this study. In 113 infants less than 1 year old undergoing urologic evaluation, the proportion of abnormal kidneys on dimercaptosuccinic acid (DMSA) scan did not differ between those with and without urinary tract infection (33% vs. 28%), suggesting that renal scarring from reflux may occur independently of bacteriuria. ⁹⁵ Renal abnormalities detectable by ultrasound are found in 1.4% of infants who are considered normal, ^2,96 compared to 6% of infants with asymptomatic bacteriuria. ⁸ However, these infants might have been detected outside the screening program as their symptoms developed.

The effectiveness of detecting asymptomatic bacteriuria in patients with indwelling or intermittent urethral catheterization, of periodic screening in patients with known urologic structural abnormalities, or of follow-up of symptomatic urinary tract infection with repeat cultures, is not discussed in this report. These forms of testing are considered within the domain of diagnostic studies for patients with existing medical or surgical conditions, rather than a part of routine screening tests for asymptomatic persons.

The American Academy of Family Physicians (AAFP) recommends periodic screening by dipstick combining leukocyte esterase and nitrite tests to detect bacteriuria in preschool children, those who are morbidly obese, persons with diabetes or a history of gestational diabetes, and persons aged 65 years and older. ⁹⁷ The recommendations of the AAFP are currently under review. The American College of Physicians recommends against routine screening of adults for asymptomatic bacteriuria with urinalysis or urine culture. ⁹⁸ The Canadian Task Force on the Periodic Health Examination recommends against routinely screening asymptomatic infants, children, elderly men, or institutionalized elderly women for bacteriuria, and found insufficient evidence to recommend for or against screening noninstitutionalized elderly women. ⁹⁹ Bright Futures does not recommend routine urinalyses in infants, children, or adolescents. ¹⁰⁰ The American Academy of Pediatrics (AAP) recommends routine urinalysis at age 5, and dipstick urinalysis for leukocytes for all adolescents, preferably at age 15 years. ¹⁰²