Clinical Inquiries

Evidence summary

Progesterone. A Cochrane meta-analysis on the use of progesterone to prevent pregnancy loss looked at a subset of 3 small RCTs that evaluated women with 3 or more pregnancy losses. Patients with primary recurrent spontaneous abortion (RSA) (no prior live births), were not differentiated from those with secondary RSA (previous live birth with subsequent miscarriages).

Progesterone administration resulted in a significant reduction in miscarriage compared with placebo (odds ratio [OR]=0.37; 95% confidence interval [CI], 0.17–0.91), independent of administration routes (oral, vaginal, or intramuscular). This benefit was lost in the larger meta-analysis when studies containing women with fewer than 3 pregnancy losses were included.¹

Human choriogonadotropin. A meta-analysis reviewed 4 trials (n=180 total) of varying methodological quality, which were constructed to determine if women, with at least 2 consecutive miscarriages of unknown cause, derive any protective effect when they receive HCG during the first trimester. Although the overall outcome favored the use of HCG (OR=0.26 compared with placebo; 95% CI, 0.14–0.52), the trials contained major methodological weaknesses (poor description of methods, no power calculations, selection and unclear randomization techniques).²

Immunotherapy. A systematic review of 22 RCTs evaluating 4 different types of immunotherapy for recurrent miscarriage found no significant improvement in live birth rates. All studies were of high quality with a low level of bias. Only one lacked double-blinding.

Immunotherapy types included: paternal leukocyte immunization (PLI) (11 trials, 596 women) (OR=1.05; 95% CI, 0.75–1.47); intravenous immune globulin (IVIG) (OR=0.98; 95% CI, 0.61–1.58); third-party donor cell immunization (3 trials, 156 women) (OR=1.39; 95% CI, 0.68–2.82); and trophoblast membrane infusion (1 trial, 37 women) (OR=0.40; 95% CI, 0.11–1.45).³

A subsequent RCT comparing PLI with placebo among 79 women with primary RSA of unknown cause again found no significant difference in live birth rates (89% vs 71%, respectively).⁴ However, an additional RCT evaluating PLI (32 patients) vs placebo (19 patients) among women with unexplained primary RSA did find significantly higher birth rates with PLI (84% vs 25%; P=.001). This small study used different techniques than previous PLI studies.⁵

A later meta-analysis of 5 RCTs including a total of 246 patients also found that IVIG did not improve the subsequent live birth rate for women with a history of primary or secondary RSA (OR=0.98; 95% CI, 0.45–2.13).⁶

Aspirin. An RCT involving 54 pregnant women (mean age 32.7 years) with a history of primary RSA of unknown cause (negative standard workup) evaluated 50 mg of aspirin daily (n=27) vs placebo (n=27).⁷ The method of blinding was not reported.

The live birth rate was identical for the 2 groups (88%). A second (unblinded) trial randomized 805 women from a large referral center (mean age 34 years) with a history of first-trimester RSA (not differentiated between primary and secondary RSA) of unknown cause to either 75 mg of aspirin daily or no treatment.⁸ There was no significant difference in the live birth rate between those who took aspirin (251/367; 68.4%) and those who did not (278/438; 63.5%; OR=1.24; 95% CI, 0.93–1.67).

Recommendations from others

The American College of Obstetricians and Gynecologists (ACOG) states that “it has not been shown conclusively that progesterone treatment or corpus luteum support (HCG) influences pregnancy outcome for women with recurrent spontaneous abortion.”⁹ ACOG does not recommend immunotherapy, citing a lack of demonstrated efficacy (IVIG and PLI), a lack of standards for cell storage and administration, and a risk profile similar to that of blood transfusion (PLI). They recommend “couples with otherwise unexplained recurrent pregnancy loss should be counseled regarding the potential for successful pregnancy without treatment.”

Evidence summary

Progesterone. A Cochrane meta-analysis on the use of progesterone to prevent pregnancy loss looked at a subset of 3 small RCTs that evaluated women with 3 or more pregnancy losses. Patients with primary recurrent spontaneous abortion (RSA) (no prior live births), were not differentiated from those with secondary RSA (previous live birth with subsequent miscarriages).

Progesterone administration resulted in a significant reduction in miscarriage compared with placebo (odds ratio [OR]=0.37; 95% confidence interval [CI], 0.17–0.91), independent of administration routes (oral, vaginal, or intramuscular). This benefit was lost in the larger meta-analysis when studies containing women with fewer than 3 pregnancy losses were included.¹

Human choriogonadotropin. A meta-analysis reviewed 4 trials (n=180 total) of varying methodological quality, which were constructed to determine if women, with at least 2 consecutive miscarriages of unknown cause, derive any protective effect when they receive HCG during the first trimester. Although the overall outcome favored the use of HCG (OR=0.26 compared with placebo; 95% CI, 0.14–0.52), the trials contained major methodological weaknesses (poor description of methods, no power calculations, selection and unclear randomization techniques).²

Immunotherapy. A systematic review of 22 RCTs evaluating 4 different types of immunotherapy for recurrent miscarriage found no significant improvement in live birth rates. All studies were of high quality with a low level of bias. Only one lacked double-blinding.

Immunotherapy types included: paternal leukocyte immunization (PLI) (11 trials, 596 women) (OR=1.05; 95% CI, 0.75–1.47); intravenous immune globulin (IVIG) (OR=0.98; 95% CI, 0.61–1.58); third-party donor cell immunization (3 trials, 156 women) (OR=1.39; 95% CI, 0.68–2.82); and trophoblast membrane infusion (1 trial, 37 women) (OR=0.40; 95% CI, 0.11–1.45).³

A subsequent RCT comparing PLI with placebo among 79 women with primary RSA of unknown cause again found no significant difference in live birth rates (89% vs 71%, respectively).⁴ However, an additional RCT evaluating PLI (32 patients) vs placebo (19 patients) among women with unexplained primary RSA did find significantly higher birth rates with PLI (84% vs 25%; P=.001). This small study used different techniques than previous PLI studies.⁵

A later meta-analysis of 5 RCTs including a total of 246 patients also found that IVIG did not improve the subsequent live birth rate for women with a history of primary or secondary RSA (OR=0.98; 95% CI, 0.45–2.13).⁶

Aspirin. An RCT involving 54 pregnant women (mean age 32.7 years) with a history of primary RSA of unknown cause (negative standard workup) evaluated 50 mg of aspirin daily (n=27) vs placebo (n=27).⁷ The method of blinding was not reported.

The live birth rate was identical for the 2 groups (88%). A second (unblinded) trial randomized 805 women from a large referral center (mean age 34 years) with a history of first-trimester RSA (not differentiated between primary and secondary RSA) of unknown cause to either 75 mg of aspirin daily or no treatment.⁸ There was no significant difference in the live birth rate between those who took aspirin (251/367; 68.4%) and those who did not (278/438; 63.5%; OR=1.24; 95% CI, 0.93–1.67).

Recommendations from others

The American College of Obstetricians and Gynecologists (ACOG) states that “it has not been shown conclusively that progesterone treatment or corpus luteum support (HCG) influences pregnancy outcome for women with recurrent spontaneous abortion.”⁹ ACOG does not recommend immunotherapy, citing a lack of demonstrated efficacy (IVIG and PLI), a lack of standards for cell storage and administration, and a risk profile similar to that of blood transfusion (PLI). They recommend “couples with otherwise unexplained recurrent pregnancy loss should be counseled regarding the potential for successful pregnancy without treatment.”

Evidence summary

Progesterone. A Cochrane meta-analysis on the use of progesterone to prevent pregnancy loss looked at a subset of 3 small RCTs that evaluated women with 3 or more pregnancy losses. Patients with primary recurrent spontaneous abortion (RSA) (no prior live births), were not differentiated from those with secondary RSA (previous live birth with subsequent miscarriages).

Progesterone administration resulted in a significant reduction in miscarriage compared with placebo (odds ratio [OR]=0.37; 95% confidence interval [CI], 0.17–0.91), independent of administration routes (oral, vaginal, or intramuscular). This benefit was lost in the larger meta-analysis when studies containing women with fewer than 3 pregnancy losses were included.¹

Human choriogonadotropin. A meta-analysis reviewed 4 trials (n=180 total) of varying methodological quality, which were constructed to determine if women, with at least 2 consecutive miscarriages of unknown cause, derive any protective effect when they receive HCG during the first trimester. Although the overall outcome favored the use of HCG (OR=0.26 compared with placebo; 95% CI, 0.14–0.52), the trials contained major methodological weaknesses (poor description of methods, no power calculations, selection and unclear randomization techniques).²

Immunotherapy. A systematic review of 22 RCTs evaluating 4 different types of immunotherapy for recurrent miscarriage found no significant improvement in live birth rates. All studies were of high quality with a low level of bias. Only one lacked double-blinding.

Immunotherapy types included: paternal leukocyte immunization (PLI) (11 trials, 596 women) (OR=1.05; 95% CI, 0.75–1.47); intravenous immune globulin (IVIG) (OR=0.98; 95% CI, 0.61–1.58); third-party donor cell immunization (3 trials, 156 women) (OR=1.39; 95% CI, 0.68–2.82); and trophoblast membrane infusion (1 trial, 37 women) (OR=0.40; 95% CI, 0.11–1.45).³

A subsequent RCT comparing PLI with placebo among 79 women with primary RSA of unknown cause again found no significant difference in live birth rates (89% vs 71%, respectively).⁴ However, an additional RCT evaluating PLI (32 patients) vs placebo (19 patients) among women with unexplained primary RSA did find significantly higher birth rates with PLI (84% vs 25%; P=.001). This small study used different techniques than previous PLI studies.⁵

A later meta-analysis of 5 RCTs including a total of 246 patients also found that IVIG did not improve the subsequent live birth rate for women with a history of primary or secondary RSA (OR=0.98; 95% CI, 0.45–2.13).⁶

Aspirin. An RCT involving 54 pregnant women (mean age 32.7 years) with a history of primary RSA of unknown cause (negative standard workup) evaluated 50 mg of aspirin daily (n=27) vs placebo (n=27).⁷ The method of blinding was not reported.

The live birth rate was identical for the 2 groups (88%). A second (unblinded) trial randomized 805 women from a large referral center (mean age 34 years) with a history of first-trimester RSA (not differentiated between primary and secondary RSA) of unknown cause to either 75 mg of aspirin daily or no treatment.⁸ There was no significant difference in the live birth rate between those who took aspirin (251/367; 68.4%) and those who did not (278/438; 63.5%; OR=1.24; 95% CI, 0.93–1.67).

Recommendations from others

The American College of Obstetricians and Gynecologists (ACOG) states that “it has not been shown conclusively that progesterone treatment or corpus luteum support (HCG) influences pregnancy outcome for women with recurrent spontaneous abortion.”⁹ ACOG does not recommend immunotherapy, citing a lack of demonstrated efficacy (IVIG and PLI), a lack of standards for cell storage and administration, and a risk profile similar to that of blood transfusion (PLI). They recommend “couples with otherwise unexplained recurrent pregnancy loss should be counseled regarding the potential for successful pregnancy without treatment.”

Evidence summary

A systematic review of 18 studies, including 3 RCTs, compared outcomes for expectant management (545 women) vs surgical evacuation (1408 women) for first-trimester spontaneous abortion.¹ A successful first-trimester spontaneous abortion was defined as vaginal bleeding for 3 weeks or less, fully expelled products of conception by 14 days, and no complications (infection, transfusion, uterine perforation, hospitalization, or death). Expectant management was successful in 93% overall, and 80% using only the data from RCTs.

An observational study evaluated 1096 consecutive patients with suspected first-trimester abortion, classified by ultrasound as complete, incomplete, missed, or anembryonic.² In the latter 3 categories, patients chose expectant management (478) or immediate surgical evacuation (208). Those choosing expectant management were monitored weekly and offered surgical evacuation if their abortion was incomplete after 1 month (TABLE). Complications arose in 6 of 451 patients (1%) managed expectantly for up to 46 days, and in 5 of 208 patients (2%) managed surgically (not statistically significant). One patient in the expectant group had emergency surgery and blood transfusion.²

A smaller observational study evaluated 108 women with first-trimester missed abortions or anembryonic pregnancies who chose either expectant (85 women) or surgical management. They were followed with weekly ultrasound (including color Doppler imaging) and serum β-hCG for up to 1 month. Fifty-three (62%) completed a spontaneous abortion at 14 days and 71 (84%) at 28 days. There were no significant differences in the rate of complications.³

A prospective trial compared psychological morbidity for 86 women with ultrasound-confirmed first-trimester missed abortions, randomized to expectant or surgical management. At 2 weeks, a self-administered questionnaire about the experience of pregnancy loss found no significant difference in psychological reactions. No increase was seen in anxiety or depression symptoms between women who had miscarried and healthy nonpregnant working women aged 19 to 39 years.⁴

Expert opinion recommends that women with spontaneous abortion beyond 13 weeks, a temperature >100.4° F, unstable blood pressure, uncontrolled vaginal bleeding, or evidence of endometritis or pelvic inflammatory disease should have surgical evacuation.²

TABLE
Completed abortions with expectant management by type²

Recommendations from others

UpToDate recommends expectant management for stable women who do not want any medical or surgical intervention, and are willing to wait for expulsion to occur. Surgical evacuation is recommended for women who are not stable because of bleeding or infection or for those who want immediate, definitive treatment of the nonviable pregnancy.⁵

Evidence summary

A systematic review of 18 studies, including 3 RCTs, compared outcomes for expectant management (545 women) vs surgical evacuation (1408 women) for first-trimester spontaneous abortion.¹ A successful first-trimester spontaneous abortion was defined as vaginal bleeding for 3 weeks or less, fully expelled products of conception by 14 days, and no complications (infection, transfusion, uterine perforation, hospitalization, or death). Expectant management was successful in 93% overall, and 80% using only the data from RCTs.

An observational study evaluated 1096 consecutive patients with suspected first-trimester abortion, classified by ultrasound as complete, incomplete, missed, or anembryonic.² In the latter 3 categories, patients chose expectant management (478) or immediate surgical evacuation (208). Those choosing expectant management were monitored weekly and offered surgical evacuation if their abortion was incomplete after 1 month (TABLE). Complications arose in 6 of 451 patients (1%) managed expectantly for up to 46 days, and in 5 of 208 patients (2%) managed surgically (not statistically significant). One patient in the expectant group had emergency surgery and blood transfusion.²

A smaller observational study evaluated 108 women with first-trimester missed abortions or anembryonic pregnancies who chose either expectant (85 women) or surgical management. They were followed with weekly ultrasound (including color Doppler imaging) and serum β-hCG for up to 1 month. Fifty-three (62%) completed a spontaneous abortion at 14 days and 71 (84%) at 28 days. There were no significant differences in the rate of complications.³

A prospective trial compared psychological morbidity for 86 women with ultrasound-confirmed first-trimester missed abortions, randomized to expectant or surgical management. At 2 weeks, a self-administered questionnaire about the experience of pregnancy loss found no significant difference in psychological reactions. No increase was seen in anxiety or depression symptoms between women who had miscarried and healthy nonpregnant working women aged 19 to 39 years.⁴

Expert opinion recommends that women with spontaneous abortion beyond 13 weeks, a temperature >100.4° F, unstable blood pressure, uncontrolled vaginal bleeding, or evidence of endometritis or pelvic inflammatory disease should have surgical evacuation.²

TABLE
Completed abortions with expectant management by type²

Recommendations from others

UpToDate recommends expectant management for stable women who do not want any medical or surgical intervention, and are willing to wait for expulsion to occur. Surgical evacuation is recommended for women who are not stable because of bleeding or infection or for those who want immediate, definitive treatment of the nonviable pregnancy.⁵

Evidence summary

A systematic review of 18 studies, including 3 RCTs, compared outcomes for expectant management (545 women) vs surgical evacuation (1408 women) for first-trimester spontaneous abortion.¹ A successful first-trimester spontaneous abortion was defined as vaginal bleeding for 3 weeks or less, fully expelled products of conception by 14 days, and no complications (infection, transfusion, uterine perforation, hospitalization, or death). Expectant management was successful in 93% overall, and 80% using only the data from RCTs.

An observational study evaluated 1096 consecutive patients with suspected first-trimester abortion, classified by ultrasound as complete, incomplete, missed, or anembryonic.² In the latter 3 categories, patients chose expectant management (478) or immediate surgical evacuation (208). Those choosing expectant management were monitored weekly and offered surgical evacuation if their abortion was incomplete after 1 month (TABLE). Complications arose in 6 of 451 patients (1%) managed expectantly for up to 46 days, and in 5 of 208 patients (2%) managed surgically (not statistically significant). One patient in the expectant group had emergency surgery and blood transfusion.²

A smaller observational study evaluated 108 women with first-trimester missed abortions or anembryonic pregnancies who chose either expectant (85 women) or surgical management. They were followed with weekly ultrasound (including color Doppler imaging) and serum β-hCG for up to 1 month. Fifty-three (62%) completed a spontaneous abortion at 14 days and 71 (84%) at 28 days. There were no significant differences in the rate of complications.³

A prospective trial compared psychological morbidity for 86 women with ultrasound-confirmed first-trimester missed abortions, randomized to expectant or surgical management. At 2 weeks, a self-administered questionnaire about the experience of pregnancy loss found no significant difference in psychological reactions. No increase was seen in anxiety or depression symptoms between women who had miscarried and healthy nonpregnant working women aged 19 to 39 years.⁴

Expert opinion recommends that women with spontaneous abortion beyond 13 weeks, a temperature >100.4° F, unstable blood pressure, uncontrolled vaginal bleeding, or evidence of endometritis or pelvic inflammatory disease should have surgical evacuation.²

TABLE
Completed abortions with expectant management by type²

Recommendations from others

UpToDate recommends expectant management for stable women who do not want any medical or surgical intervention, and are willing to wait for expulsion to occur. Surgical evacuation is recommended for women who are not stable because of bleeding or infection or for those who want immediate, definitive treatment of the nonviable pregnancy.⁵

Evidence summary

More than two thirds of people aged >50 years have experienced leg cramps.¹ Though leg cramps are common, little is known about their actual causation.^2,3

A small, retrospective chart review, limited to male patients, identified an association of vascular and neurologic diseases among patients taking quinine, presumably for leg cramps.² Although commonly idiopathic, leg cramps are sometimes associated with various disorders including endocrine, metabolic, occupational, structural, neuromuscular, vascular, and congenital disorders, as well as toxin- and drug-related causes (TABLE).^4,5 All reviews suggest that the best diagnostic approach to leg cramps is a thorough history, and careful physical and neurological examination.^1,3,4 The health care provider should clarify the onset and duration of leg cramps, any precipitating activity, and factors that provide relief. A detailed history should focus on precipitating factors for iron deficiency anemia (gastro-intestinal bleeding, frequent blood donations, menorrhagia), a history of renal disease (especially end-stage renal failure) and medication use (antidepressants and diuretics).

The physical examination should include a search for obvious physical signs of symptoms noted in the history.⁶ Neurological examination can exclude most disorders that simulate leg cramps such as contractures, dystonia, myalgia and peripheral neuropathy.^1,2,4

The choice of laboratory investigations such as ferritin, electrolytes, blood sugar, magnesium, zinc, creatinine, blood urea nitrogen, liver function test, and thyroid function test are largely governed by the findings from the history and physical examination.¹ Though neurophysiological research shows that true muscle cramps are caused by explosive hyperactivity of motor nerves, using diagnostic tools such as electromyography, muscle biopsy, and muscle enzymes are seldom needed.⁷

Because of the lack of well-designed, randomized controlled studies, this diagnostic approach is based on nonsystematic reviews, and may differ for individuals based on history and clinical examination.

TABLE
Possible causes of leg cramps

Recommendations from others

UpToDate states, “a careful history and examination can exclude the majority of disorders in the differential diagnosis” of leg cramps.⁷

Evidence summary

More than two thirds of people aged >50 years have experienced leg cramps.¹ Though leg cramps are common, little is known about their actual causation.^2,3

A small, retrospective chart review, limited to male patients, identified an association of vascular and neurologic diseases among patients taking quinine, presumably for leg cramps.² Although commonly idiopathic, leg cramps are sometimes associated with various disorders including endocrine, metabolic, occupational, structural, neuromuscular, vascular, and congenital disorders, as well as toxin- and drug-related causes (TABLE).^4,5 All reviews suggest that the best diagnostic approach to leg cramps is a thorough history, and careful physical and neurological examination.^1,3,4 The health care provider should clarify the onset and duration of leg cramps, any precipitating activity, and factors that provide relief. A detailed history should focus on precipitating factors for iron deficiency anemia (gastro-intestinal bleeding, frequent blood donations, menorrhagia), a history of renal disease (especially end-stage renal failure) and medication use (antidepressants and diuretics).

The physical examination should include a search for obvious physical signs of symptoms noted in the history.⁶ Neurological examination can exclude most disorders that simulate leg cramps such as contractures, dystonia, myalgia and peripheral neuropathy.^1,2,4

The choice of laboratory investigations such as ferritin, electrolytes, blood sugar, magnesium, zinc, creatinine, blood urea nitrogen, liver function test, and thyroid function test are largely governed by the findings from the history and physical examination.¹ Though neurophysiological research shows that true muscle cramps are caused by explosive hyperactivity of motor nerves, using diagnostic tools such as electromyography, muscle biopsy, and muscle enzymes are seldom needed.⁷

Because of the lack of well-designed, randomized controlled studies, this diagnostic approach is based on nonsystematic reviews, and may differ for individuals based on history and clinical examination.

TABLE
Possible causes of leg cramps

Recommendations from others

UpToDate states, “a careful history and examination can exclude the majority of disorders in the differential diagnosis” of leg cramps.⁷

Evidence summary

More than two thirds of people aged >50 years have experienced leg cramps.¹ Though leg cramps are common, little is known about their actual causation.^2,3

A small, retrospective chart review, limited to male patients, identified an association of vascular and neurologic diseases among patients taking quinine, presumably for leg cramps.² Although commonly idiopathic, leg cramps are sometimes associated with various disorders including endocrine, metabolic, occupational, structural, neuromuscular, vascular, and congenital disorders, as well as toxin- and drug-related causes (TABLE).^4,5 All reviews suggest that the best diagnostic approach to leg cramps is a thorough history, and careful physical and neurological examination.^1,3,4 The health care provider should clarify the onset and duration of leg cramps, any precipitating activity, and factors that provide relief. A detailed history should focus on precipitating factors for iron deficiency anemia (gastro-intestinal bleeding, frequent blood donations, menorrhagia), a history of renal disease (especially end-stage renal failure) and medication use (antidepressants and diuretics).

The physical examination should include a search for obvious physical signs of symptoms noted in the history.⁶ Neurological examination can exclude most disorders that simulate leg cramps such as contractures, dystonia, myalgia and peripheral neuropathy.^1,2,4

The choice of laboratory investigations such as ferritin, electrolytes, blood sugar, magnesium, zinc, creatinine, blood urea nitrogen, liver function test, and thyroid function test are largely governed by the findings from the history and physical examination.¹ Though neurophysiological research shows that true muscle cramps are caused by explosive hyperactivity of motor nerves, using diagnostic tools such as electromyography, muscle biopsy, and muscle enzymes are seldom needed.⁷

Because of the lack of well-designed, randomized controlled studies, this diagnostic approach is based on nonsystematic reviews, and may differ for individuals based on history and clinical examination.

TABLE
Possible causes of leg cramps

Recommendations from others

UpToDate states, “a careful history and examination can exclude the majority of disorders in the differential diagnosis” of leg cramps.⁷

Evidence summary

Five randomized controlled trials have examined lung cancer mortality after screening chest x-rays. In the first trial—the only one that included former as well as current smokers and nonsmokers—subjects were randomized to undergo chest x-ray studies every 6 months, or at baseline and again at the end of the 3-year study. After 3 years, there was no statistically significant mortality difference with more frequent chest x-rays.^1,2

Another trial involved male smokers who were randomized to undergo chest x-ray and sputum cytology either every 6 months or after 3 years. After 3 years, both groups were screened annually with chest x-ray alone for an additional 3 years. There was no significant difference in lung cancer mortality at any point, including at a 15-year post-trial follow-up.³Both studies showed earlier detection and longer survivorship of lung cancer among screened vs nonscreened groups due to lead-time bias (because the cancer was detected earlier from screening vs clinical diagnosis, it falsely appears to prolong survival). Overall mortality was the same in both groups.

The National Cancer Institute (NCI) sponsored 3 randomized controlled trials on lung cancer screening for male smokers involving 3 major medical centers. The studies were designed to determine the incremental benefit of adding sputum cytology to chest x-ray screening. In 2 of the NCI studies, participants were randomly assigned to receive annual chest x-ray only or a dual screen with annual chest x-ray and sputum cytologies every 4 months. In both studies, there was no statistical difference in lung cancer mortality between the 2 groups.^4-6The third NCI study randomized participants to chest x-ray and sputum cytology either every 4 months or annually. Again, there was no significant difference in lung cancer mortality,⁴even after an extended follow-up of 20.5 years.⁷Adding sputum cytology to chest x-ray only improved lung cancer detection rates over chest x-ray alone.

A significant limitation of the 5 studies presented is that no true control or non-screening groups determined the real efficacy of screening chest x-rays vs no screening. The goal of a study of a screening program is to detect a disease early enough so that treatment can alter mortality. These uncontrolled studies of routine screening chest x-rays, no matter how frequently performed, do not meet this criteria for current and former smokers.

Recommendations from others

The US Preventive Services Task Force does not recommend for or against screening asymptomatic or high-risk persons for lung cancer with either low-dose computed tomography (CT), chest x-ray, sputum cytology, or a combination of these tests.⁸ The American Cancer Society and American Academy of Family Physicians recommend against the use of chest x-ray or sputum cytology in asymptomatic high-risk persons.^9,10The American College of Chest Physicians recommends against the use of serial chest x-rays for individuals without symptoms or without a history of cancer.¹¹ They do not comment about high-risk groups—that is, current or former smokers.

Evidence summary

Five randomized controlled trials have examined lung cancer mortality after screening chest x-rays. In the first trial—the only one that included former as well as current smokers and nonsmokers—subjects were randomized to undergo chest x-ray studies every 6 months, or at baseline and again at the end of the 3-year study. After 3 years, there was no statistically significant mortality difference with more frequent chest x-rays.^1,2

Another trial involved male smokers who were randomized to undergo chest x-ray and sputum cytology either every 6 months or after 3 years. After 3 years, both groups were screened annually with chest x-ray alone for an additional 3 years. There was no significant difference in lung cancer mortality at any point, including at a 15-year post-trial follow-up.³Both studies showed earlier detection and longer survivorship of lung cancer among screened vs nonscreened groups due to lead-time bias (because the cancer was detected earlier from screening vs clinical diagnosis, it falsely appears to prolong survival). Overall mortality was the same in both groups.

The National Cancer Institute (NCI) sponsored 3 randomized controlled trials on lung cancer screening for male smokers involving 3 major medical centers. The studies were designed to determine the incremental benefit of adding sputum cytology to chest x-ray screening. In 2 of the NCI studies, participants were randomly assigned to receive annual chest x-ray only or a dual screen with annual chest x-ray and sputum cytologies every 4 months. In both studies, there was no statistical difference in lung cancer mortality between the 2 groups.^4-6The third NCI study randomized participants to chest x-ray and sputum cytology either every 4 months or annually. Again, there was no significant difference in lung cancer mortality,⁴even after an extended follow-up of 20.5 years.⁷Adding sputum cytology to chest x-ray only improved lung cancer detection rates over chest x-ray alone.

A significant limitation of the 5 studies presented is that no true control or non-screening groups determined the real efficacy of screening chest x-rays vs no screening. The goal of a study of a screening program is to detect a disease early enough so that treatment can alter mortality. These uncontrolled studies of routine screening chest x-rays, no matter how frequently performed, do not meet this criteria for current and former smokers.

Recommendations from others

The US Preventive Services Task Force does not recommend for or against screening asymptomatic or high-risk persons for lung cancer with either low-dose computed tomography (CT), chest x-ray, sputum cytology, or a combination of these tests.⁸ The American Cancer Society and American Academy of Family Physicians recommend against the use of chest x-ray or sputum cytology in asymptomatic high-risk persons.^9,10The American College of Chest Physicians recommends against the use of serial chest x-rays for individuals without symptoms or without a history of cancer.¹¹ They do not comment about high-risk groups—that is, current or former smokers.

Evidence summary

Five randomized controlled trials have examined lung cancer mortality after screening chest x-rays. In the first trial—the only one that included former as well as current smokers and nonsmokers—subjects were randomized to undergo chest x-ray studies every 6 months, or at baseline and again at the end of the 3-year study. After 3 years, there was no statistically significant mortality difference with more frequent chest x-rays.^1,2

Another trial involved male smokers who were randomized to undergo chest x-ray and sputum cytology either every 6 months or after 3 years. After 3 years, both groups were screened annually with chest x-ray alone for an additional 3 years. There was no significant difference in lung cancer mortality at any point, including at a 15-year post-trial follow-up.³Both studies showed earlier detection and longer survivorship of lung cancer among screened vs nonscreened groups due to lead-time bias (because the cancer was detected earlier from screening vs clinical diagnosis, it falsely appears to prolong survival). Overall mortality was the same in both groups.

The National Cancer Institute (NCI) sponsored 3 randomized controlled trials on lung cancer screening for male smokers involving 3 major medical centers. The studies were designed to determine the incremental benefit of adding sputum cytology to chest x-ray screening. In 2 of the NCI studies, participants were randomly assigned to receive annual chest x-ray only or a dual screen with annual chest x-ray and sputum cytologies every 4 months. In both studies, there was no statistical difference in lung cancer mortality between the 2 groups.^4-6The third NCI study randomized participants to chest x-ray and sputum cytology either every 4 months or annually. Again, there was no significant difference in lung cancer mortality,⁴even after an extended follow-up of 20.5 years.⁷Adding sputum cytology to chest x-ray only improved lung cancer detection rates over chest x-ray alone.

A significant limitation of the 5 studies presented is that no true control or non-screening groups determined the real efficacy of screening chest x-rays vs no screening. The goal of a study of a screening program is to detect a disease early enough so that treatment can alter mortality. These uncontrolled studies of routine screening chest x-rays, no matter how frequently performed, do not meet this criteria for current and former smokers.

Recommendations from others

The US Preventive Services Task Force does not recommend for or against screening asymptomatic or high-risk persons for lung cancer with either low-dose computed tomography (CT), chest x-ray, sputum cytology, or a combination of these tests.⁸ The American Cancer Society and American Academy of Family Physicians recommend against the use of chest x-ray or sputum cytology in asymptomatic high-risk persons.^9,10The American College of Chest Physicians recommends against the use of serial chest x-rays for individuals without symptoms or without a history of cancer.¹¹ They do not comment about high-risk groups—that is, current or former smokers.

Evidence summary

“Early” diagnosis of renovascular hypertension is best defined as diagnosis while blood pressure is controlled by medications or when renal function remains normal.

Hypertension. A meta-analysis (3 RCTs, total n=210 patients) examining balloon angioplasty for RAS and poorly controlled hypertension showed modest but significant effect on blood pressure control.¹ Comparing the angioplasty group with medical management, the mean reduction in blood pressure was –7 mm Hg systolic (95% confidence interval [CI], –12 to –1) and –3 mm Hg diastolic (95% CI, –6 to –1). Patients treated with balloon angioplasty were more likely to use fewer antihypertensive medications (unable to synthesize data for quantity) and to have fewer major cardiovascular and renovascular complications (not defined specifically) (odds ratio [OR]=0.27; 95% CI, 0.06–1.23; P=.09).¹ One cohort study of 150 patients found that stenting bilateral (vs unilateral) RAS predicted a more beneficial blood pressure response (OR=4.6; P=.009).²

Renal impairment. The value of RAS intervention for patients with hypertension and worsening renal function is unclear. One RCT of 106 patients with atherosclerotic RAS and serum creatinine (Cr) of <2.3 mg/dL compared PTRA with medical therapy of hypertension. By an intentionto-treat analysis, there was no significant difference in renal function at 12 months between the groups.³ A nonblinded RCT of 85 patients found no change in mortality or renal function with intervention. Three groups were compared: observation of 52 patients with unilateral RAS (>50%), intervention on 12 patients with bilateral RAS, and observation of 21 patients with bilateral RAS. All groups reported 32% mortality at 2 years. Only 3 of the 27 deaths were directly related to renal disease (2 from the observation group with unilateral RAS and one from the intervention group).⁴ Cohor studies, using different measures of renal function, report improvement, stabilization, or worsening following intervention.^5-7

Congestive heart failure and flash pulmonary edema. Patients who have recurrent episodes of congestive heart failure or flash pulmonary edema with severe RAS have marked functional improvement following PTRA with stenting. One retrospective cohort study (n=39) reported a decrease in hospitalizations (from 2.4 ±1.4 per year to 0.3 ±0.7 per year; P<.001) and improvement in New York Heart Association heart failure functional classification (2.9 ±0.9 to 1.6 ±0.9).⁸

Diagnosis. MRA (sensitivity 99%, specificity 93%) and CT angiography (sensitivity 97%, specificity 95%) are the most accurate and cost-effective, based on a large meta-analysis.⁹

Complications. Serious or potentially serious complications (ie, bleeding, renal artery injury, need for hemodialysis) were seen in 13% to 25% of patients who underwent angioplasty.^2,5,7 Combining 3 studies (n=632), there were 5 procedurerelated deaths.^5,7,10

Worsened patient survival correlated with Cr >1.7 mg/dL or age >70 (OR=9.96, P<.0001 and OR=3.4, P=.001, respectively). Worsened renal survival was present in the same subgroups (OR=7.8, P<.001 and OR=2.7, P<.01, respectively).⁷

Recommendations from others

The American Heart Association lists 3 clinical criteria for revascularization: 1) hypertension (accelerated, refractory, or malignant), 2) renal salvage, 3) cardiac disturbance syndromes (recurrent “flash” pulmonary edema or unstable angina with significant RAS).¹¹ JNC 7 does not recommend looking for RAS unless hypertension is uncontrollable.¹²

The Society of Nuclear Medicine recommends that only moderate- to high-risk individuals be screened for RAS. This guideline clarifies that RAS does not equal renovascular hypertension and that the future “gold standard” diagnosis of renovascular hypertension should be the response to successful revascularization.¹³

Evidence summary

“Early” diagnosis of renovascular hypertension is best defined as diagnosis while blood pressure is controlled by medications or when renal function remains normal.

Hypertension. A meta-analysis (3 RCTs, total n=210 patients) examining balloon angioplasty for RAS and poorly controlled hypertension showed modest but significant effect on blood pressure control.¹ Comparing the angioplasty group with medical management, the mean reduction in blood pressure was –7 mm Hg systolic (95% confidence interval [CI], –12 to –1) and –3 mm Hg diastolic (95% CI, –6 to –1). Patients treated with balloon angioplasty were more likely to use fewer antihypertensive medications (unable to synthesize data for quantity) and to have fewer major cardiovascular and renovascular complications (not defined specifically) (odds ratio [OR]=0.27; 95% CI, 0.06–1.23; P=.09).¹ One cohort study of 150 patients found that stenting bilateral (vs unilateral) RAS predicted a more beneficial blood pressure response (OR=4.6; P=.009).²

Renal impairment. The value of RAS intervention for patients with hypertension and worsening renal function is unclear. One RCT of 106 patients with atherosclerotic RAS and serum creatinine (Cr) of <2.3 mg/dL compared PTRA with medical therapy of hypertension. By an intentionto-treat analysis, there was no significant difference in renal function at 12 months between the groups.³ A nonblinded RCT of 85 patients found no change in mortality or renal function with intervention. Three groups were compared: observation of 52 patients with unilateral RAS (>50%), intervention on 12 patients with bilateral RAS, and observation of 21 patients with bilateral RAS. All groups reported 32% mortality at 2 years. Only 3 of the 27 deaths were directly related to renal disease (2 from the observation group with unilateral RAS and one from the intervention group).⁴ Cohor studies, using different measures of renal function, report improvement, stabilization, or worsening following intervention.^5-7

Congestive heart failure and flash pulmonary edema. Patients who have recurrent episodes of congestive heart failure or flash pulmonary edema with severe RAS have marked functional improvement following PTRA with stenting. One retrospective cohort study (n=39) reported a decrease in hospitalizations (from 2.4 ±1.4 per year to 0.3 ±0.7 per year; P<.001) and improvement in New York Heart Association heart failure functional classification (2.9 ±0.9 to 1.6 ±0.9).⁸

Diagnosis. MRA (sensitivity 99%, specificity 93%) and CT angiography (sensitivity 97%, specificity 95%) are the most accurate and cost-effective, based on a large meta-analysis.⁹

Complications. Serious or potentially serious complications (ie, bleeding, renal artery injury, need for hemodialysis) were seen in 13% to 25% of patients who underwent angioplasty.^2,5,7 Combining 3 studies (n=632), there were 5 procedurerelated deaths.^5,7,10

Worsened patient survival correlated with Cr >1.7 mg/dL or age >70 (OR=9.96, P<.0001 and OR=3.4, P=.001, respectively). Worsened renal survival was present in the same subgroups (OR=7.8, P<.001 and OR=2.7, P<.01, respectively).⁷

Recommendations from others

The American Heart Association lists 3 clinical criteria for revascularization: 1) hypertension (accelerated, refractory, or malignant), 2) renal salvage, 3) cardiac disturbance syndromes (recurrent “flash” pulmonary edema or unstable angina with significant RAS).¹¹ JNC 7 does not recommend looking for RAS unless hypertension is uncontrollable.¹²

The Society of Nuclear Medicine recommends that only moderate- to high-risk individuals be screened for RAS. This guideline clarifies that RAS does not equal renovascular hypertension and that the future “gold standard” diagnosis of renovascular hypertension should be the response to successful revascularization.¹³

Evidence summary

“Early” diagnosis of renovascular hypertension is best defined as diagnosis while blood pressure is controlled by medications or when renal function remains normal.

Hypertension. A meta-analysis (3 RCTs, total n=210 patients) examining balloon angioplasty for RAS and poorly controlled hypertension showed modest but significant effect on blood pressure control.¹ Comparing the angioplasty group with medical management, the mean reduction in blood pressure was –7 mm Hg systolic (95% confidence interval [CI], –12 to –1) and –3 mm Hg diastolic (95% CI, –6 to –1). Patients treated with balloon angioplasty were more likely to use fewer antihypertensive medications (unable to synthesize data for quantity) and to have fewer major cardiovascular and renovascular complications (not defined specifically) (odds ratio [OR]=0.27; 95% CI, 0.06–1.23; P=.09).¹ One cohort study of 150 patients found that stenting bilateral (vs unilateral) RAS predicted a more beneficial blood pressure response (OR=4.6; P=.009).²

Renal impairment. The value of RAS intervention for patients with hypertension and worsening renal function is unclear. One RCT of 106 patients with atherosclerotic RAS and serum creatinine (Cr) of <2.3 mg/dL compared PTRA with medical therapy of hypertension. By an intentionto-treat analysis, there was no significant difference in renal function at 12 months between the groups.³ A nonblinded RCT of 85 patients found no change in mortality or renal function with intervention. Three groups were compared: observation of 52 patients with unilateral RAS (>50%), intervention on 12 patients with bilateral RAS, and observation of 21 patients with bilateral RAS. All groups reported 32% mortality at 2 years. Only 3 of the 27 deaths were directly related to renal disease (2 from the observation group with unilateral RAS and one from the intervention group).⁴ Cohor studies, using different measures of renal function, report improvement, stabilization, or worsening following intervention.^5-7

Congestive heart failure and flash pulmonary edema. Patients who have recurrent episodes of congestive heart failure or flash pulmonary edema with severe RAS have marked functional improvement following PTRA with stenting. One retrospective cohort study (n=39) reported a decrease in hospitalizations (from 2.4 ±1.4 per year to 0.3 ±0.7 per year; P<.001) and improvement in New York Heart Association heart failure functional classification (2.9 ±0.9 to 1.6 ±0.9).⁸

Diagnosis. MRA (sensitivity 99%, specificity 93%) and CT angiography (sensitivity 97%, specificity 95%) are the most accurate and cost-effective, based on a large meta-analysis.⁹

Complications. Serious or potentially serious complications (ie, bleeding, renal artery injury, need for hemodialysis) were seen in 13% to 25% of patients who underwent angioplasty.^2,5,7 Combining 3 studies (n=632), there were 5 procedurerelated deaths.^5,7,10

Worsened patient survival correlated with Cr >1.7 mg/dL or age >70 (OR=9.96, P<.0001 and OR=3.4, P=.001, respectively). Worsened renal survival was present in the same subgroups (OR=7.8, P<.001 and OR=2.7, P<.01, respectively).⁷

Recommendations from others

The American Heart Association lists 3 clinical criteria for revascularization: 1) hypertension (accelerated, refractory, or malignant), 2) renal salvage, 3) cardiac disturbance syndromes (recurrent “flash” pulmonary edema or unstable angina with significant RAS).¹¹ JNC 7 does not recommend looking for RAS unless hypertension is uncontrollable.¹²

The Society of Nuclear Medicine recommends that only moderate- to high-risk individuals be screened for RAS. This guideline clarifies that RAS does not equal renovascular hypertension and that the future “gold standard” diagnosis of renovascular hypertension should be the response to successful revascularization.¹³

Evidence summary

There are currently no large outcome studies evaluating the initial work-up of hypertension; however, 4 international expert panels have published recommendations.^2-5 These panels advise 3 initial objectives: 1) assess lifestyle and identify other cardiovascular risk factors or concomitant disorders that may affect prognosis and guide treatment; 2) search for treatable causes of high blood pressure; and 3) assess for the presence of target organ damage that would change the management of the patient (such as chronic kidney disease or heart disease).

In addition to a thorough history and physical, the following studies are recommended for patients with newly diagnosed hypertension:

Serum potassium and creatinine. All 4 panels recommend measuring serum potassium and creatinine in order to: 1) monitor the effects of diuretics and angiotensin-converting enzyme (ACE) inhibitors used in hypertension therapy, 2) screen for unexplained hypokalemia that may indicate a low-renin form of hypertension, 3) calculate baseline creatinine clearance, and 4) screen for chronic kidney disease.

Fasting blood glucose. All 4 panels recommend measuring a fasting glucose level to screen for diabetes. An abnormal glucose level may also reveal glucose intolerance, one of the diagnostic criteria of metabolic syndrome. Up to 60% of patients with diabetes also have hypertension.⁶

Fasting lipid panel. All 4 expert panels recommend screening for dyslipidemia with a fasting lipid panel to assess cardiovascular risk. A cohort study evaluating 356,222 men aged 35 to 57 years found a continuous, positive, graded correlation between plasma cholesterol levels and coronary risk.⁷

Hematocrit. All 4 panels recommend a hematocrit to screen for anemia, which may be due to chronic kidney disease.

Urinalysis. All 4 panels recommend a urinalysis to screen for renal disease.

Electrocardiogram (ECG). All 4 panels recommend an ECG to screen for findings associated with hypertension, including left ventricular hypertrophy (LVH), myocardial infarction, and rhythm abnormalities. A cohort study followed 2363 patients for 14 years who had untreated hypertension and were without pre-existing cardiovascular disease. After controlling for age, sex, diabetes, and mean blood pressure, LVH by ECG conferred a significant increased risk for cerebrovascular events (relative risk=1.79; 95% confidence interval [CI], 1.17–2.76).⁸ However, in a cohort of 4684 subjects from the Framingham Heart Study, ECG had a sensitivity of only 6.9% for the detection of LVH (specificity 98.8%; positive likelihood ratio=5.3; negative likelihood ratio=0.94).⁸

Echocardiography. Two panels^3,4 and an online text¹⁰ recommend echocardiography, preferably limited echo, as an optional study. A systematic review of studies comparing the sensitivities and specificities of ECG and echo found that each was highly specific for the detection of LVH (77%–97%), but the sensitivity of echocardiography (88%–93%) exceeded that of ECG (21%–54%). However, LVH detected by ECG is a better predictor of cardiovascular complications.¹¹ Because echocardiography may help assess disease duration and guide management, both panels recommend it for patients with severe or refractory hypertension but without other target organ damage.

Microalbuminuria. All panels listed microalbuminuria testing as an optional study for patients without diabetes because of its association with an increased incidence of cerebrovascular disease.¹² It is unclear whether microalbuminuria results from the increased intraglomerular pressure in hypertension or if it represents glomerular damage.¹³

Sodium, calcium, uric acid. There is no consensus on the routine inclusion of several studies: serum sodium (recommended by 2 panels and an online text^4,5,10 ), serum calcium (recommended by 1 panel and the text^2,10), and uric acid (1 panel³ recommends it while the text¹⁰ lists it as optional).

Recommendations from others

Recommendations from major organizations are included in Evidence Summary, above.

Acknowledgments

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

Evidence summary

There are currently no large outcome studies evaluating the initial work-up of hypertension; however, 4 international expert panels have published recommendations.^2-5 These panels advise 3 initial objectives: 1) assess lifestyle and identify other cardiovascular risk factors or concomitant disorders that may affect prognosis and guide treatment; 2) search for treatable causes of high blood pressure; and 3) assess for the presence of target organ damage that would change the management of the patient (such as chronic kidney disease or heart disease).

In addition to a thorough history and physical, the following studies are recommended for patients with newly diagnosed hypertension:

Serum potassium and creatinine. All 4 panels recommend measuring serum potassium and creatinine in order to: 1) monitor the effects of diuretics and angiotensin-converting enzyme (ACE) inhibitors used in hypertension therapy, 2) screen for unexplained hypokalemia that may indicate a low-renin form of hypertension, 3) calculate baseline creatinine clearance, and 4) screen for chronic kidney disease.

Fasting blood glucose. All 4 panels recommend measuring a fasting glucose level to screen for diabetes. An abnormal glucose level may also reveal glucose intolerance, one of the diagnostic criteria of metabolic syndrome. Up to 60% of patients with diabetes also have hypertension.⁶

Fasting lipid panel. All 4 expert panels recommend screening for dyslipidemia with a fasting lipid panel to assess cardiovascular risk. A cohort study evaluating 356,222 men aged 35 to 57 years found a continuous, positive, graded correlation between plasma cholesterol levels and coronary risk.⁷

Hematocrit. All 4 panels recommend a hematocrit to screen for anemia, which may be due to chronic kidney disease.

Urinalysis. All 4 panels recommend a urinalysis to screen for renal disease.

Electrocardiogram (ECG). All 4 panels recommend an ECG to screen for findings associated with hypertension, including left ventricular hypertrophy (LVH), myocardial infarction, and rhythm abnormalities. A cohort study followed 2363 patients for 14 years who had untreated hypertension and were without pre-existing cardiovascular disease. After controlling for age, sex, diabetes, and mean blood pressure, LVH by ECG conferred a significant increased risk for cerebrovascular events (relative risk=1.79; 95% confidence interval [CI], 1.17–2.76).⁸ However, in a cohort of 4684 subjects from the Framingham Heart Study, ECG had a sensitivity of only 6.9% for the detection of LVH (specificity 98.8%; positive likelihood ratio=5.3; negative likelihood ratio=0.94).⁸

Echocardiography. Two panels^3,4 and an online text¹⁰ recommend echocardiography, preferably limited echo, as an optional study. A systematic review of studies comparing the sensitivities and specificities of ECG and echo found that each was highly specific for the detection of LVH (77%–97%), but the sensitivity of echocardiography (88%–93%) exceeded that of ECG (21%–54%). However, LVH detected by ECG is a better predictor of cardiovascular complications.¹¹ Because echocardiography may help assess disease duration and guide management, both panels recommend it for patients with severe or refractory hypertension but without other target organ damage.

Microalbuminuria. All panels listed microalbuminuria testing as an optional study for patients without diabetes because of its association with an increased incidence of cerebrovascular disease.¹² It is unclear whether microalbuminuria results from the increased intraglomerular pressure in hypertension or if it represents glomerular damage.¹³

Sodium, calcium, uric acid. There is no consensus on the routine inclusion of several studies: serum sodium (recommended by 2 panels and an online text^4,5,10 ), serum calcium (recommended by 1 panel and the text^2,10), and uric acid (1 panel³ recommends it while the text¹⁰ lists it as optional).

Recommendations from others

Recommendations from major organizations are included in Evidence Summary, above.

Acknowledgments

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

Evidence summary

There are currently no large outcome studies evaluating the initial work-up of hypertension; however, 4 international expert panels have published recommendations.^2-5 These panels advise 3 initial objectives: 1) assess lifestyle and identify other cardiovascular risk factors or concomitant disorders that may affect prognosis and guide treatment; 2) search for treatable causes of high blood pressure; and 3) assess for the presence of target organ damage that would change the management of the patient (such as chronic kidney disease or heart disease).

In addition to a thorough history and physical, the following studies are recommended for patients with newly diagnosed hypertension:

Serum potassium and creatinine. All 4 panels recommend measuring serum potassium and creatinine in order to: 1) monitor the effects of diuretics and angiotensin-converting enzyme (ACE) inhibitors used in hypertension therapy, 2) screen for unexplained hypokalemia that may indicate a low-renin form of hypertension, 3) calculate baseline creatinine clearance, and 4) screen for chronic kidney disease.

Fasting blood glucose. All 4 panels recommend measuring a fasting glucose level to screen for diabetes. An abnormal glucose level may also reveal glucose intolerance, one of the diagnostic criteria of metabolic syndrome. Up to 60% of patients with diabetes also have hypertension.⁶

Fasting lipid panel. All 4 expert panels recommend screening for dyslipidemia with a fasting lipid panel to assess cardiovascular risk. A cohort study evaluating 356,222 men aged 35 to 57 years found a continuous, positive, graded correlation between plasma cholesterol levels and coronary risk.⁷

Hematocrit. All 4 panels recommend a hematocrit to screen for anemia, which may be due to chronic kidney disease.

Urinalysis. All 4 panels recommend a urinalysis to screen for renal disease.

Electrocardiogram (ECG). All 4 panels recommend an ECG to screen for findings associated with hypertension, including left ventricular hypertrophy (LVH), myocardial infarction, and rhythm abnormalities. A cohort study followed 2363 patients for 14 years who had untreated hypertension and were without pre-existing cardiovascular disease. After controlling for age, sex, diabetes, and mean blood pressure, LVH by ECG conferred a significant increased risk for cerebrovascular events (relative risk=1.79; 95% confidence interval [CI], 1.17–2.76).⁸ However, in a cohort of 4684 subjects from the Framingham Heart Study, ECG had a sensitivity of only 6.9% for the detection of LVH (specificity 98.8%; positive likelihood ratio=5.3; negative likelihood ratio=0.94).⁸

Echocardiography. Two panels^3,4 and an online text¹⁰ recommend echocardiography, preferably limited echo, as an optional study. A systematic review of studies comparing the sensitivities and specificities of ECG and echo found that each was highly specific for the detection of LVH (77%–97%), but the sensitivity of echocardiography (88%–93%) exceeded that of ECG (21%–54%). However, LVH detected by ECG is a better predictor of cardiovascular complications.¹¹ Because echocardiography may help assess disease duration and guide management, both panels recommend it for patients with severe or refractory hypertension but without other target organ damage.

Microalbuminuria. All panels listed microalbuminuria testing as an optional study for patients without diabetes because of its association with an increased incidence of cerebrovascular disease.¹² It is unclear whether microalbuminuria results from the increased intraglomerular pressure in hypertension or if it represents glomerular damage.¹³

Sodium, calcium, uric acid. There is no consensus on the routine inclusion of several studies: serum sodium (recommended by 2 panels and an online text^4,5,10 ), serum calcium (recommended by 1 panel and the text^2,10), and uric acid (1 panel³ recommends it while the text¹⁰ lists it as optional).

Recommendations from others

Recommendations from major organizations are included in Evidence Summary, above.

Acknowledgments

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

Evidence summary

The risks and benefits associated with progestin-only contraceptives are not completely studied for all routes of administration. There is insufficient evidence regarding their risks to point to a definitive harm with their administration (TABLE).

The risk of pregnancy with progestinonly contraceptives ranges from 0.0% to 13.2% based on the method that is selected.⁸ Evidence is lacking to support use of progestin-only contraceptives for premenstrual syndrome or dysfunctional uterine bleeding.^6,7

TABLE
Risks and benefits of progestin-only contraceptives

Recommendations from others

The World Health Organization (WHO) highlights the need to avoid progestin-only contraceptives for women younger than 18 or older than 45 years, secondary to concerns of decreased bone mass. Immediately postpartum, women may initiate progestinonly contraceptives if they are not breast-feeding; if breastfeeding, women should wait until at least 6 months postpartum.

Hypertensive women should avoid progestin-only contraceptives; women at risk for hypertension—particularly DMPA users—are encouraged to measure blood pressure before and after use. The WHO document points out the increased possibility for abnormal uterine bleeding with progestin-only contraceptives use.⁹

American College of Physician’s PIER: Physicians’ Information and Education Resource describes using progestin-only contraceptives in hypercoagulable states and severe hyperlipidemia and avoiding use in osteoporosis, osteopenia, and chronic glucocorticoid use due to a decrease in bone mineral density.¹⁰

The American College of Obstetricians and Gynecologists (ACOG) specifically endorses the preferential use of progestin-only contraceptives by lactating women and women at an increased risk of venous thromboembolism based on good evidence. For women with systemic lupus erythematosus, ACOG recommends use of progestin-only contraceptives over combined oral contraceptive, based on fair evidence. By consensus, ACOG recognizes benefits of DMPA for women with sickle-cell disease and women with coronary artery disease, congestive heart failure, or cerebrovascular disease. In general, ACOG recommends progestin-only contraceptives over combined oral contraceptives for patients with the following conditions: migraine headaches, cigarette smoker of age greater than 35, history of venous thromboembolism, coronary artery disease, congestive heart failure, cerebrovascular disease, postpartum <2 weeks, hypertension with vascular disease or age greater than 35, diabetes with vascular disease or age greater than 35, systemic lupus erythematosus with vascular disease, nephritis, or antiphospholipid antibodies, or hypertriglyceridemia.¹¹

Evidence summary

The risks and benefits associated with progestin-only contraceptives are not completely studied for all routes of administration. There is insufficient evidence regarding their risks to point to a definitive harm with their administration (TABLE).

The risk of pregnancy with progestinonly contraceptives ranges from 0.0% to 13.2% based on the method that is selected.⁸ Evidence is lacking to support use of progestin-only contraceptives for premenstrual syndrome or dysfunctional uterine bleeding.^6,7

TABLE
Risks and benefits of progestin-only contraceptives

Recommendations from others

The World Health Organization (WHO) highlights the need to avoid progestin-only contraceptives for women younger than 18 or older than 45 years, secondary to concerns of decreased bone mass. Immediately postpartum, women may initiate progestinonly contraceptives if they are not breast-feeding; if breastfeeding, women should wait until at least 6 months postpartum.

Hypertensive women should avoid progestin-only contraceptives; women at risk for hypertension—particularly DMPA users—are encouraged to measure blood pressure before and after use. The WHO document points out the increased possibility for abnormal uterine bleeding with progestin-only contraceptives use.⁹

American College of Physician’s PIER: Physicians’ Information and Education Resource describes using progestin-only contraceptives in hypercoagulable states and severe hyperlipidemia and avoiding use in osteoporosis, osteopenia, and chronic glucocorticoid use due to a decrease in bone mineral density.¹⁰

The American College of Obstetricians and Gynecologists (ACOG) specifically endorses the preferential use of progestin-only contraceptives by lactating women and women at an increased risk of venous thromboembolism based on good evidence. For women with systemic lupus erythematosus, ACOG recommends use of progestin-only contraceptives over combined oral contraceptive, based on fair evidence. By consensus, ACOG recognizes benefits of DMPA for women with sickle-cell disease and women with coronary artery disease, congestive heart failure, or cerebrovascular disease. In general, ACOG recommends progestin-only contraceptives over combined oral contraceptives for patients with the following conditions: migraine headaches, cigarette smoker of age greater than 35, history of venous thromboembolism, coronary artery disease, congestive heart failure, cerebrovascular disease, postpartum <2 weeks, hypertension with vascular disease or age greater than 35, diabetes with vascular disease or age greater than 35, systemic lupus erythematosus with vascular disease, nephritis, or antiphospholipid antibodies, or hypertriglyceridemia.¹¹

Evidence summary

The risks and benefits associated with progestin-only contraceptives are not completely studied for all routes of administration. There is insufficient evidence regarding their risks to point to a definitive harm with their administration (TABLE).

The risk of pregnancy with progestinonly contraceptives ranges from 0.0% to 13.2% based on the method that is selected.⁸ Evidence is lacking to support use of progestin-only contraceptives for premenstrual syndrome or dysfunctional uterine bleeding.^6,7

TABLE
Risks and benefits of progestin-only contraceptives

Recommendations from others

The World Health Organization (WHO) highlights the need to avoid progestin-only contraceptives for women younger than 18 or older than 45 years, secondary to concerns of decreased bone mass. Immediately postpartum, women may initiate progestinonly contraceptives if they are not breast-feeding; if breastfeeding, women should wait until at least 6 months postpartum.

Hypertensive women should avoid progestin-only contraceptives; women at risk for hypertension—particularly DMPA users—are encouraged to measure blood pressure before and after use. The WHO document points out the increased possibility for abnormal uterine bleeding with progestin-only contraceptives use.⁹

American College of Physician’s PIER: Physicians’ Information and Education Resource describes using progestin-only contraceptives in hypercoagulable states and severe hyperlipidemia and avoiding use in osteoporosis, osteopenia, and chronic glucocorticoid use due to a decrease in bone mineral density.¹⁰

The American College of Obstetricians and Gynecologists (ACOG) specifically endorses the preferential use of progestin-only contraceptives by lactating women and women at an increased risk of venous thromboembolism based on good evidence. For women with systemic lupus erythematosus, ACOG recommends use of progestin-only contraceptives over combined oral contraceptive, based on fair evidence. By consensus, ACOG recognizes benefits of DMPA for women with sickle-cell disease and women with coronary artery disease, congestive heart failure, or cerebrovascular disease. In general, ACOG recommends progestin-only contraceptives over combined oral contraceptives for patients with the following conditions: migraine headaches, cigarette smoker of age greater than 35, history of venous thromboembolism, coronary artery disease, congestive heart failure, cerebrovascular disease, postpartum <2 weeks, hypertension with vascular disease or age greater than 35, diabetes with vascular disease or age greater than 35, systemic lupus erythematosus with vascular disease, nephritis, or antiphospholipid antibodies, or hypertriglyceridemia.¹¹

Evidence summary

Breast cancer is the second leading cause of cancer death among American women; 1 in 8 women will be diagnosed with breast cancer in her lifetime, and 1 in 30 will die of it.³ Breast cancer screening and mammography have become almost synonymous. But physical examinations by clinicians or women themselves remain important methods of screening to consider.

Breast self-examination is appealing as a patient-centered, inexpensive, noninvasive procedure that empowers women and is universally available. However, a recent Cochrane review found no evidence of benefit from self-screening.

Two large RCTs, conducted in St Petersburg, Russia (122,471 women) and Shanghai, China (266,064 women), were found. Both studies used cluster randomization (by worksite) and involved large numbers of women who were meticulously trained in proper breast self-examination technique and had numerousreinforcement sessions. Study compliance and follow-up were excellent. Outcomes assessment was explicitly blinded in the Shanghai study. Neither trial demonstrated a reduction in breast cancer mortality or improvement in the number or stage of cancers detected during 9 to 11 years of follow-up, but there is evidence for harm: a nearly 2-fold increase in false-positive results, physician visits, and biopsies for benign disease.⁴

No trials comparing screening clinical breast examinations alone to no screening have been reported, but good indirect evidence of efficacy comes from the results of the Canadian National Breast Screening Study-2 (CNBSS-2).⁵ A total of 39,405 women aged 50 to 59 years were randomized to screening with clinical exams plus mammography or clinical exams alone. Other large RCTs have shown a consistent benefit to mammography screening for women of this age (in-depth independent reviews of recent criticism of the trials have concluded that their flaws do not negate mammography’s efficacy in reducing breast cancer mortality).^3,6 The CNBSS-2 trial showed no mortality advantage when mammography was added to an annual, standardized 10- to 15-minute breast examination, implying that careful, detailed, annual clinical breast examinations may be as effective as a mammography screening program.³

Recommendations from others

The US Preventive Services Task Force found insufficient evidence to recommend for or against routine clinical exams alone to screen for breast cancer, or to recommend for or against teaching or performing routine breast self-examination.³ The Canadian Task Force on Preventive Health Services recommends against teaching self-examination to women aged 40 to 69 years due to “fair evidence of no benefit and good evidence of harm.”^7,8

The American Cancer Society continues to recommend periodic clinical exams,⁶ and women who choose to do self-examination should receive instruction and have their technique reviewed during periodic health examinations; it is acceptable for women to choose not to do self-examinations. The American Academy of Family Physicians concludes that the evidence is insufficient to recommend for or against breast self-examination.⁹ The American College of Obstetricians and Gynecologists recommends both.¹⁰

Evidence summary

Breast cancer is the second leading cause of cancer death among American women; 1 in 8 women will be diagnosed with breast cancer in her lifetime, and 1 in 30 will die of it.³ Breast cancer screening and mammography have become almost synonymous. But physical examinations by clinicians or women themselves remain important methods of screening to consider.

Breast self-examination is appealing as a patient-centered, inexpensive, noninvasive procedure that empowers women and is universally available. However, a recent Cochrane review found no evidence of benefit from self-screening.

Two large RCTs, conducted in St Petersburg, Russia (122,471 women) and Shanghai, China (266,064 women), were found. Both studies used cluster randomization (by worksite) and involved large numbers of women who were meticulously trained in proper breast self-examination technique and had numerousreinforcement sessions. Study compliance and follow-up were excellent. Outcomes assessment was explicitly blinded in the Shanghai study. Neither trial demonstrated a reduction in breast cancer mortality or improvement in the number or stage of cancers detected during 9 to 11 years of follow-up, but there is evidence for harm: a nearly 2-fold increase in false-positive results, physician visits, and biopsies for benign disease.⁴

No trials comparing screening clinical breast examinations alone to no screening have been reported, but good indirect evidence of efficacy comes from the results of the Canadian National Breast Screening Study-2 (CNBSS-2).⁵ A total of 39,405 women aged 50 to 59 years were randomized to screening with clinical exams plus mammography or clinical exams alone. Other large RCTs have shown a consistent benefit to mammography screening for women of this age (in-depth independent reviews of recent criticism of the trials have concluded that their flaws do not negate mammography’s efficacy in reducing breast cancer mortality).^3,6 The CNBSS-2 trial showed no mortality advantage when mammography was added to an annual, standardized 10- to 15-minute breast examination, implying that careful, detailed, annual clinical breast examinations may be as effective as a mammography screening program.³

Recommendations from others

The US Preventive Services Task Force found insufficient evidence to recommend for or against routine clinical exams alone to screen for breast cancer, or to recommend for or against teaching or performing routine breast self-examination.³ The Canadian Task Force on Preventive Health Services recommends against teaching self-examination to women aged 40 to 69 years due to “fair evidence of no benefit and good evidence of harm.”^7,8

The American Cancer Society continues to recommend periodic clinical exams,⁶ and women who choose to do self-examination should receive instruction and have their technique reviewed during periodic health examinations; it is acceptable for women to choose not to do self-examinations. The American Academy of Family Physicians concludes that the evidence is insufficient to recommend for or against breast self-examination.⁹ The American College of Obstetricians and Gynecologists recommends both.¹⁰

Evidence summary

Breast cancer is the second leading cause of cancer death among American women; 1 in 8 women will be diagnosed with breast cancer in her lifetime, and 1 in 30 will die of it.³ Breast cancer screening and mammography have become almost synonymous. But physical examinations by clinicians or women themselves remain important methods of screening to consider.

Breast self-examination is appealing as a patient-centered, inexpensive, noninvasive procedure that empowers women and is universally available. However, a recent Cochrane review found no evidence of benefit from self-screening.

Two large RCTs, conducted in St Petersburg, Russia (122,471 women) and Shanghai, China (266,064 women), were found. Both studies used cluster randomization (by worksite) and involved large numbers of women who were meticulously trained in proper breast self-examination technique and had numerousreinforcement sessions. Study compliance and follow-up were excellent. Outcomes assessment was explicitly blinded in the Shanghai study. Neither trial demonstrated a reduction in breast cancer mortality or improvement in the number or stage of cancers detected during 9 to 11 years of follow-up, but there is evidence for harm: a nearly 2-fold increase in false-positive results, physician visits, and biopsies for benign disease.⁴

No trials comparing screening clinical breast examinations alone to no screening have been reported, but good indirect evidence of efficacy comes from the results of the Canadian National Breast Screening Study-2 (CNBSS-2).⁵ A total of 39,405 women aged 50 to 59 years were randomized to screening with clinical exams plus mammography or clinical exams alone. Other large RCTs have shown a consistent benefit to mammography screening for women of this age (in-depth independent reviews of recent criticism of the trials have concluded that their flaws do not negate mammography’s efficacy in reducing breast cancer mortality).^3,6 The CNBSS-2 trial showed no mortality advantage when mammography was added to an annual, standardized 10- to 15-minute breast examination, implying that careful, detailed, annual clinical breast examinations may be as effective as a mammography screening program.³

Recommendations from others

The US Preventive Services Task Force found insufficient evidence to recommend for or against routine clinical exams alone to screen for breast cancer, or to recommend for or against teaching or performing routine breast self-examination.³ The Canadian Task Force on Preventive Health Services recommends against teaching self-examination to women aged 40 to 69 years due to “fair evidence of no benefit and good evidence of harm.”^7,8

The American Cancer Society continues to recommend periodic clinical exams,⁶ and women who choose to do self-examination should receive instruction and have their technique reviewed during periodic health examinations; it is acceptable for women to choose not to do self-examinations. The American Academy of Family Physicians concludes that the evidence is insufficient to recommend for or against breast self-examination.⁹ The American College of Obstetricians and Gynecologists recommends both.¹⁰

Evidence summary

In the United States, approximately 5000 infants with moderate-to-profound hearing loss are born annually.¹ Affected children graduate high school averaging 4th-grade academic performance skills.² Efforts to reduce the impact on these children have focused on early diagnosis and treatment.

A systematic review gathered studies comparing universal hearing screening with selective screening.¹ Most included studies used a 2-stage universal screening protocol. Infants who failed initial testing were retested within 12 weeks. Testing methods included otoacoustic emissions (OAE) and auditory brainstem response (ABR). Infants who failed the second test were referred for audiological evaluation. Using these data, a hypothetical model was created, which found that 1441 newborns would need to be screened to diagnose 1 additional case of moderate-to-profound permanent hearing loss before 10 months of age (at cost of 200 extra referrals for false-positives). Sensitivity and specificity of the hypothetical model’s 2-stage screening was 85% and 97%, respectively. The estimated positive predictive value was 6.7%.^1,3

Individually, OAE and ABR accurately diagnose neonatal hearing loss. One multicenter cohort of 2995 infants measured test performance of OAE and ABR against the gold standard (visual reinforcement audiometry performed at 8–12 months).⁴ The authors used a receiver operating characteristics (ROC) curve to plot speech awareness thresholds for both tests. When middle-ear pathology and progressive hearing loss were excluded, the area under the ROC curves for ABR and OAE were 0.91 and 0.94, respectively, indication that both tests had excellent test accuracy (a perfect test would have an area under the curve of 1.0).

Strategies based on selective screening of high-risk infants fails to identify permanent hearing loss in many affected infants. In a cohort study of more than 10,000 infants, only 43% of infants with permanent hearing loss were identified with selective versus universal screening. Most affected infants would have been missed using risk-based criteria.⁵

Limited evidence suggests that early identification of infants with permanent hearing loss improves language skills. In a retrospective cohort study of 150 infants examining language outcomes, participants were grouped according to age at identification of hearing loss.⁶ All participants received comprehensive in-home language intervention services plus amplification devices.

Of the 85 children with normal cognitive ability, the mean receptive and expressive language quotients at 13 to 36 months were higher in the early-identified group vs the late-identified group (receptive language quotients, 79.6 vs 64.6, P<.001; expressive language quotients, 78.3 vs 63.1, P<.001). Total language quotient was also higher in the early group (language quotients, 79 vs 64; P<.001).

The conclusions were limited by multiple factors: retrospective study design, cohort selection drawn from different hospitals during different time periods, unblinded participant selection, and unblended outcome assessments. Other published studies have inconclusive outcome data. The Cochrane Collaboration published a systematic review in which no studies were found that fulfilled the inclusion criteria to evaluate the effectiveness of universal hearing screening.⁷

Recommendations from others

The Joint Committee on Infant Hearing recommended universal neonatal hearing screening during hospital birth admission in their Year 2000 Position Statement.⁸ For infants whose hearing is impaired on re-screening, the committee recommends audiology referral and medical evaluation to rule out associated conditions before age 3 months. They further recommend interventional services begin before age 6 months for infants with confirmed hearing loss.

The US Preventive Services Task Force does not recommend for or against universal hearing screening, citing insufficient outcomes data.⁹

Evidence summary

In the United States, approximately 5000 infants with moderate-to-profound hearing loss are born annually.¹ Affected children graduate high school averaging 4th-grade academic performance skills.² Efforts to reduce the impact on these children have focused on early diagnosis and treatment.

A systematic review gathered studies comparing universal hearing screening with selective screening.¹ Most included studies used a 2-stage universal screening protocol. Infants who failed initial testing were retested within 12 weeks. Testing methods included otoacoustic emissions (OAE) and auditory brainstem response (ABR). Infants who failed the second test were referred for audiological evaluation. Using these data, a hypothetical model was created, which found that 1441 newborns would need to be screened to diagnose 1 additional case of moderate-to-profound permanent hearing loss before 10 months of age (at cost of 200 extra referrals for false-positives). Sensitivity and specificity of the hypothetical model’s 2-stage screening was 85% and 97%, respectively. The estimated positive predictive value was 6.7%.^1,3

Individually, OAE and ABR accurately diagnose neonatal hearing loss. One multicenter cohort of 2995 infants measured test performance of OAE and ABR against the gold standard (visual reinforcement audiometry performed at 8–12 months).⁴ The authors used a receiver operating characteristics (ROC) curve to plot speech awareness thresholds for both tests. When middle-ear pathology and progressive hearing loss were excluded, the area under the ROC curves for ABR and OAE were 0.91 and 0.94, respectively, indication that both tests had excellent test accuracy (a perfect test would have an area under the curve of 1.0).

Strategies based on selective screening of high-risk infants fails to identify permanent hearing loss in many affected infants. In a cohort study of more than 10,000 infants, only 43% of infants with permanent hearing loss were identified with selective versus universal screening. Most affected infants would have been missed using risk-based criteria.⁵

Limited evidence suggests that early identification of infants with permanent hearing loss improves language skills. In a retrospective cohort study of 150 infants examining language outcomes, participants were grouped according to age at identification of hearing loss.⁶ All participants received comprehensive in-home language intervention services plus amplification devices.

Of the 85 children with normal cognitive ability, the mean receptive and expressive language quotients at 13 to 36 months were higher in the early-identified group vs the late-identified group (receptive language quotients, 79.6 vs 64.6, P<.001; expressive language quotients, 78.3 vs 63.1, P<.001). Total language quotient was also higher in the early group (language quotients, 79 vs 64; P<.001).

The conclusions were limited by multiple factors: retrospective study design, cohort selection drawn from different hospitals during different time periods, unblinded participant selection, and unblended outcome assessments. Other published studies have inconclusive outcome data. The Cochrane Collaboration published a systematic review in which no studies were found that fulfilled the inclusion criteria to evaluate the effectiveness of universal hearing screening.⁷

Recommendations from others

The Joint Committee on Infant Hearing recommended universal neonatal hearing screening during hospital birth admission in their Year 2000 Position Statement.⁸ For infants whose hearing is impaired on re-screening, the committee recommends audiology referral and medical evaluation to rule out associated conditions before age 3 months. They further recommend interventional services begin before age 6 months for infants with confirmed hearing loss.

The US Preventive Services Task Force does not recommend for or against universal hearing screening, citing insufficient outcomes data.⁹

Evidence summary

In the United States, approximately 5000 infants with moderate-to-profound hearing loss are born annually.¹ Affected children graduate high school averaging 4th-grade academic performance skills.² Efforts to reduce the impact on these children have focused on early diagnosis and treatment.

A systematic review gathered studies comparing universal hearing screening with selective screening.¹ Most included studies used a 2-stage universal screening protocol. Infants who failed initial testing were retested within 12 weeks. Testing methods included otoacoustic emissions (OAE) and auditory brainstem response (ABR). Infants who failed the second test were referred for audiological evaluation. Using these data, a hypothetical model was created, which found that 1441 newborns would need to be screened to diagnose 1 additional case of moderate-to-profound permanent hearing loss before 10 months of age (at cost of 200 extra referrals for false-positives). Sensitivity and specificity of the hypothetical model’s 2-stage screening was 85% and 97%, respectively. The estimated positive predictive value was 6.7%.^1,3

Individually, OAE and ABR accurately diagnose neonatal hearing loss. One multicenter cohort of 2995 infants measured test performance of OAE and ABR against the gold standard (visual reinforcement audiometry performed at 8–12 months).⁴ The authors used a receiver operating characteristics (ROC) curve to plot speech awareness thresholds for both tests. When middle-ear pathology and progressive hearing loss were excluded, the area under the ROC curves for ABR and OAE were 0.91 and 0.94, respectively, indication that both tests had excellent test accuracy (a perfect test would have an area under the curve of 1.0).

Strategies based on selective screening of high-risk infants fails to identify permanent hearing loss in many affected infants. In a cohort study of more than 10,000 infants, only 43% of infants with permanent hearing loss were identified with selective versus universal screening. Most affected infants would have been missed using risk-based criteria.⁵

Limited evidence suggests that early identification of infants with permanent hearing loss improves language skills. In a retrospective cohort study of 150 infants examining language outcomes, participants were grouped according to age at identification of hearing loss.⁶ All participants received comprehensive in-home language intervention services plus amplification devices.

Of the 85 children with normal cognitive ability, the mean receptive and expressive language quotients at 13 to 36 months were higher in the early-identified group vs the late-identified group (receptive language quotients, 79.6 vs 64.6, P<.001; expressive language quotients, 78.3 vs 63.1, P<.001). Total language quotient was also higher in the early group (language quotients, 79 vs 64; P<.001).

The conclusions were limited by multiple factors: retrospective study design, cohort selection drawn from different hospitals during different time periods, unblinded participant selection, and unblended outcome assessments. Other published studies have inconclusive outcome data. The Cochrane Collaboration published a systematic review in which no studies were found that fulfilled the inclusion criteria to evaluate the effectiveness of universal hearing screening.⁷

Recommendations from others

The Joint Committee on Infant Hearing recommended universal neonatal hearing screening during hospital birth admission in their Year 2000 Position Statement.⁸ For infants whose hearing is impaired on re-screening, the committee recommends audiology referral and medical evaluation to rule out associated conditions before age 3 months. They further recommend interventional services begin before age 6 months for infants with confirmed hearing loss.

The US Preventive Services Task Force does not recommend for or against universal hearing screening, citing insufficient outcomes data.⁹

Evidence summary

Though individual studies have suggested that therapy based on endoscopy performed before any other study (early endoscopy) may be superior to empiric antisecretory therapy and as efficacious as a “test and treat” strategy in symptom relief, a Cochrane systematic review of 20 RCTs (11 in primary care settings) provides the best evidence on the role of early endoscopy.¹

A subgroup analysis of 5 RCTs, which compared early endoscopy with empiric antisecretory therapy (typically for 4 weeks), revealed that early endoscopy demonstrated a trend towards improvement in self-reported symptoms and in dyspepsia symptom relief scores, but the difference was not statistically significant (relative risk [RR]=0.89; 95% confidence interval [CI], 0.77–1.1). Because each study used different symptom scores, the relative risk as calculated may under-represent the true benefit of early endoscopy when compared with empiric antisecretory therapy.

When patient satisfaction was evaluated, results were dependent on the location of care. In a primary care setting, patients undergoing early endoscopy were as satisfied as those receiving empiric antisecretory therapy.² In a trial of 414 patients randomized after referral to specialty care, patients in the early endoscopy group were more satisfied with their medical care than those receiving empiric antisecretory therapy (RR=0.13; 95% CI, 0.06–0.29).³

Results from studies comparing the benefits of H pylori “test and treat” strategies to early endoscopy are conflicting. A subgroup analysis reported on 3 RCTs from both primary and secondary settings with 931 patients comparing H pylori “test and treat” to initial endoscopy. It found no significant difference in symptom reduction (RR=1.06; 95% CI, 0.98–1.26).¹ A recent follow-up study of 1 of the trials included in the Cochrane systematic review reported on outcomes of a “test and treat” vs early endoscopy strategy at 6 years. There was no difference in days without symptoms demonstrated between the 2 groups (mean difference=0.05; 95% CI, –0.03 to 0.14 days).⁴ Self-reported symptom tracking and a poor response rate (62%) to patient questionnaires reduces the strength of this study’s conclusions.

Formal cost-effective analyses comparing the “test and treat” with early endoscopy strategy have not been done. A subgroup analysis of 4 trials from the Cochrane review (1 from primary care) demonstrated a significant reduction of the number of endoscopies among patients receiving “test and treat” care vs those receiving early endoscopy (RR=0.23; 95% CI, 0.12–0.44). In the long-term follow-up study, fewer antisecretory medication prescriptions were needed by those patients in the “test and treat” group (P=.047).⁴ These figures are more robust; they were obtained from national registry data rather than personal recall and questionnaire submission.

Recommendations from others

Guidelines from the American Gastroenterological Association for the initial approach to young patients with dyspepsia without alarm symptoms is to first “test and treat” for those testing positive for H pylori, prescribe empiric antisecretory therapy for those testing negative, and proceed with endoscopy for recurrent or persistent dyspepsia at 4 to 8 weeks.⁵ The American Society for Gastrointestinal Endoscopy does not recommend any of initial endoscopy, empiric antisecretory therapy, or “test and treat” over another for the reduction of symptoms.⁶ The British Society of Gastroenterology recommends that initial management of dyspepsia consist of empiric acid suppression and H pylori testing. Persons testing positive for H pylori should undergo endoscopy.⁷ The Institute for Clinical Systems Improvement recommends nonurgent upper endoscopy for those aged 50 years and older with symptoms of uncomplicated dyspepsia. They recommend initial H pylori testing and treating those with positive results, and empiric proton pump inhibitor treatment for 4 weeks for those who are H pylori–negative.⁸

Evidence summary

Though individual studies have suggested that therapy based on endoscopy performed before any other study (early endoscopy) may be superior to empiric antisecretory therapy and as efficacious as a “test and treat” strategy in symptom relief, a Cochrane systematic review of 20 RCTs (11 in primary care settings) provides the best evidence on the role of early endoscopy.¹

A subgroup analysis of 5 RCTs, which compared early endoscopy with empiric antisecretory therapy (typically for 4 weeks), revealed that early endoscopy demonstrated a trend towards improvement in self-reported symptoms and in dyspepsia symptom relief scores, but the difference was not statistically significant (relative risk [RR]=0.89; 95% confidence interval [CI], 0.77–1.1). Because each study used different symptom scores, the relative risk as calculated may under-represent the true benefit of early endoscopy when compared with empiric antisecretory therapy.

When patient satisfaction was evaluated, results were dependent on the location of care. In a primary care setting, patients undergoing early endoscopy were as satisfied as those receiving empiric antisecretory therapy.² In a trial of 414 patients randomized after referral to specialty care, patients in the early endoscopy group were more satisfied with their medical care than those receiving empiric antisecretory therapy (RR=0.13; 95% CI, 0.06–0.29).³

Results from studies comparing the benefits of H pylori “test and treat” strategies to early endoscopy are conflicting. A subgroup analysis reported on 3 RCTs from both primary and secondary settings with 931 patients comparing H pylori “test and treat” to initial endoscopy. It found no significant difference in symptom reduction (RR=1.06; 95% CI, 0.98–1.26).¹ A recent follow-up study of 1 of the trials included in the Cochrane systematic review reported on outcomes of a “test and treat” vs early endoscopy strategy at 6 years. There was no difference in days without symptoms demonstrated between the 2 groups (mean difference=0.05; 95% CI, –0.03 to 0.14 days).⁴ Self-reported symptom tracking and a poor response rate (62%) to patient questionnaires reduces the strength of this study’s conclusions.

Formal cost-effective analyses comparing the “test and treat” with early endoscopy strategy have not been done. A subgroup analysis of 4 trials from the Cochrane review (1 from primary care) demonstrated a significant reduction of the number of endoscopies among patients receiving “test and treat” care vs those receiving early endoscopy (RR=0.23; 95% CI, 0.12–0.44). In the long-term follow-up study, fewer antisecretory medication prescriptions were needed by those patients in the “test and treat” group (P=.047).⁴ These figures are more robust; they were obtained from national registry data rather than personal recall and questionnaire submission.

Recommendations from others

Guidelines from the American Gastroenterological Association for the initial approach to young patients with dyspepsia without alarm symptoms is to first “test and treat” for those testing positive for H pylori, prescribe empiric antisecretory therapy for those testing negative, and proceed with endoscopy for recurrent or persistent dyspepsia at 4 to 8 weeks.⁵ The American Society for Gastrointestinal Endoscopy does not recommend any of initial endoscopy, empiric antisecretory therapy, or “test and treat” over another for the reduction of symptoms.⁶ The British Society of Gastroenterology recommends that initial management of dyspepsia consist of empiric acid suppression and H pylori testing. Persons testing positive for H pylori should undergo endoscopy.⁷ The Institute for Clinical Systems Improvement recommends nonurgent upper endoscopy for those aged 50 years and older with symptoms of uncomplicated dyspepsia. They recommend initial H pylori testing and treating those with positive results, and empiric proton pump inhibitor treatment for 4 weeks for those who are H pylori–negative.⁸

Evidence summary

Though individual studies have suggested that therapy based on endoscopy performed before any other study (early endoscopy) may be superior to empiric antisecretory therapy and as efficacious as a “test and treat” strategy in symptom relief, a Cochrane systematic review of 20 RCTs (11 in primary care settings) provides the best evidence on the role of early endoscopy.¹

A subgroup analysis of 5 RCTs, which compared early endoscopy with empiric antisecretory therapy (typically for 4 weeks), revealed that early endoscopy demonstrated a trend towards improvement in self-reported symptoms and in dyspepsia symptom relief scores, but the difference was not statistically significant (relative risk [RR]=0.89; 95% confidence interval [CI], 0.77–1.1). Because each study used different symptom scores, the relative risk as calculated may under-represent the true benefit of early endoscopy when compared with empiric antisecretory therapy.

When patient satisfaction was evaluated, results were dependent on the location of care. In a primary care setting, patients undergoing early endoscopy were as satisfied as those receiving empiric antisecretory therapy.² In a trial of 414 patients randomized after referral to specialty care, patients in the early endoscopy group were more satisfied with their medical care than those receiving empiric antisecretory therapy (RR=0.13; 95% CI, 0.06–0.29).³

Results from studies comparing the benefits of H pylori “test and treat” strategies to early endoscopy are conflicting. A subgroup analysis reported on 3 RCTs from both primary and secondary settings with 931 patients comparing H pylori “test and treat” to initial endoscopy. It found no significant difference in symptom reduction (RR=1.06; 95% CI, 0.98–1.26).¹ A recent follow-up study of 1 of the trials included in the Cochrane systematic review reported on outcomes of a “test and treat” vs early endoscopy strategy at 6 years. There was no difference in days without symptoms demonstrated between the 2 groups (mean difference=0.05; 95% CI, –0.03 to 0.14 days).⁴ Self-reported symptom tracking and a poor response rate (62%) to patient questionnaires reduces the strength of this study’s conclusions.

Formal cost-effective analyses comparing the “test and treat” with early endoscopy strategy have not been done. A subgroup analysis of 4 trials from the Cochrane review (1 from primary care) demonstrated a significant reduction of the number of endoscopies among patients receiving “test and treat” care vs those receiving early endoscopy (RR=0.23; 95% CI, 0.12–0.44). In the long-term follow-up study, fewer antisecretory medication prescriptions were needed by those patients in the “test and treat” group (P=.047).⁴ These figures are more robust; they were obtained from national registry data rather than personal recall and questionnaire submission.

Recommendations from others

Guidelines from the American Gastroenterological Association for the initial approach to young patients with dyspepsia without alarm symptoms is to first “test and treat” for those testing positive for H pylori, prescribe empiric antisecretory therapy for those testing negative, and proceed with endoscopy for recurrent or persistent dyspepsia at 4 to 8 weeks.⁵ The American Society for Gastrointestinal Endoscopy does not recommend any of initial endoscopy, empiric antisecretory therapy, or “test and treat” over another for the reduction of symptoms.⁶ The British Society of Gastroenterology recommends that initial management of dyspepsia consist of empiric acid suppression and H pylori testing. Persons testing positive for H pylori should undergo endoscopy.⁷ The Institute for Clinical Systems Improvement recommends nonurgent upper endoscopy for those aged 50 years and older with symptoms of uncomplicated dyspepsia. They recommend initial H pylori testing and treating those with positive results, and empiric proton pump inhibitor treatment for 4 weeks for those who are H pylori–negative.⁸