Fran Kovach, MLIS, AHIP

Evidence summary

A population-based cohort study centered in Olmsted County, Minn (N=50,080 births between 1966 and 1995) established a baseline rate of VTE among pregnant patients (105 total events; 0.2% incidence), and found an increased relative risk of VTE among pregnant and postpartum patients (RR=4.29; 95% confidence interval [CI], 3.49-5.22; P<.001) compared with nonpregnant patients. The incidence of VTE was 199.7 per 100,000 woman-years. The postpartum annual incidence of VTE was 5 times higher than antepartum (511.2 vs 95.8 per 100,000).¹

Thrombophilia testing typically isn’t useful
There is no evidence of improved outcomes from screening pregnant women with prior VTEs for some of the more common hypercoagulable conditions, including factor V Leiden, prothrombin G20210A mutation, protein C and S deficiency, and antiphospholipid syndrome. A recent Clinical Inquiry addressed this question for general medical patients with idiopathic deep venous thrombosis and found no quality evidence to support a thrombophilia work-up in most patients.² A subsequent review, which addressed pregnant patients specifically, made the same recommendation, that is, no quality evidence supports a thrombophilia work-up in patients at risk for VTE.³

How effective is prophylactic anticoagulation?
A meta-analysis in the American College of Chest Physicians (ACCP) Evidence-Based Clinical Practice Guidelines reviewing data from 1953 orthopedic and medical patients who were mostly postoperative (and not including pregnant women) found that prophylactic anticoagulation with LMWH for patients at risk for VTE produced a relative risk for recurrent VTE of 0.36 (95% CI, 0.20-0.67).⁴

In a more recent prospective cohort study, prophylactic LMWH was given to 177 of 286 (62% treated) patients according to risk-based scoring for recurrent VTE.⁵ The treatment protocol called for anticoagulation antepartum, postpartum, or both, depending on risk score (the higher the risk, the longer the period of thromboprophylaxis). Patients with previous pregnancy-associated VTE received both antepartum and postpartum anticoagulation. The study found recurrent VTE rates of 0.35% (95% CI, 0-1.03) antepartum and 0.7% (95% CI, 0-1.67) postpartum among treated patients.⁵

Data from an earlier report summarized the expected VTE rate in patients not exposed to anticoagulation prophylaxis. This prospective cohort study evaluated 125 pregnant women with a history of prior VTE who had anticoagulation withheld and determined the rate of recurrent antepartum and postpartum VTE. Three women had an antepartum VTE (2.4%; 95% CI, 0.2-6.9). Three additional women developed postpartum VTE, for a total of 6 VTEs (4.8%, no CI reported).⁶

LMWH is beneficial, but dosing can be tricky
Patients with a history of pregnancy-associated VTE—whether or not they have known thrombophilia—do benefit from routine ante- and postpartum thromboprophylaxis, per expert opinion in practice guidelines.^4,7,8 LMWH is the preferred agent because of its safety during pregnancy and ease of dosing.

Precise dosing is nonetheless difficult to determine because clinical studies in pregnant patients are lacking and renal clearance of LMWH increases during pregnancy. Most authors recommend doses between the prophylactic and therapeutic ranges.⁴ Subcutaneous enoxaparin, for example, can be given at 40 mg every 24 hours (more aggressive, thus higher-risk, dosing is as much as 1 mg/kg every 12 hours); dalteparin can be administered at 5000 units every 24 hours up to as much as 100 units/kg every 12 hours.⁹

Recommendations

The American College of Obstetricians and Gynecologists (ACOG) 2011 updated Practice Bulletin recommends thrombophilia testing for pregnant patients previously diagnosed with a pregnancy-associated VTE, although they acknowledge the lack of quality evidence to support this recommendation. ACOG also recommends ante- and postpartum thromboprophylaxis for such patients.⁹

The ACCP expert review recommends that all pregnant women diagnosed with VTE during a previous pregnancy wear graduated elastic compression stockings throughout pregnancy and for at least 6 weeks postpartum.⁷

The ACCP also recommends LMWH for all pregnant patients with a prior VTE. Additionally, the ACCP says that a thrombophilia work-up, while not routinely recommended, might be appropriate—contingent on additional risk assessment.⁷

Evidence summary

A population-based cohort study centered in Olmsted County, Minn (N=50,080 births between 1966 and 1995) established a baseline rate of VTE among pregnant patients (105 total events; 0.2% incidence), and found an increased relative risk of VTE among pregnant and postpartum patients (RR=4.29; 95% confidence interval [CI], 3.49-5.22; P<.001) compared with nonpregnant patients. The incidence of VTE was 199.7 per 100,000 woman-years. The postpartum annual incidence of VTE was 5 times higher than antepartum (511.2 vs 95.8 per 100,000).¹

Thrombophilia testing typically isn’t useful
There is no evidence of improved outcomes from screening pregnant women with prior VTEs for some of the more common hypercoagulable conditions, including factor V Leiden, prothrombin G20210A mutation, protein C and S deficiency, and antiphospholipid syndrome. A recent Clinical Inquiry addressed this question for general medical patients with idiopathic deep venous thrombosis and found no quality evidence to support a thrombophilia work-up in most patients.² A subsequent review, which addressed pregnant patients specifically, made the same recommendation, that is, no quality evidence supports a thrombophilia work-up in patients at risk for VTE.³

How effective is prophylactic anticoagulation?
A meta-analysis in the American College of Chest Physicians (ACCP) Evidence-Based Clinical Practice Guidelines reviewing data from 1953 orthopedic and medical patients who were mostly postoperative (and not including pregnant women) found that prophylactic anticoagulation with LMWH for patients at risk for VTE produced a relative risk for recurrent VTE of 0.36 (95% CI, 0.20-0.67).⁴

In a more recent prospective cohort study, prophylactic LMWH was given to 177 of 286 (62% treated) patients according to risk-based scoring for recurrent VTE.⁵ The treatment protocol called for anticoagulation antepartum, postpartum, or both, depending on risk score (the higher the risk, the longer the period of thromboprophylaxis). Patients with previous pregnancy-associated VTE received both antepartum and postpartum anticoagulation. The study found recurrent VTE rates of 0.35% (95% CI, 0-1.03) antepartum and 0.7% (95% CI, 0-1.67) postpartum among treated patients.⁵

Data from an earlier report summarized the expected VTE rate in patients not exposed to anticoagulation prophylaxis. This prospective cohort study evaluated 125 pregnant women with a history of prior VTE who had anticoagulation withheld and determined the rate of recurrent antepartum and postpartum VTE. Three women had an antepartum VTE (2.4%; 95% CI, 0.2-6.9). Three additional women developed postpartum VTE, for a total of 6 VTEs (4.8%, no CI reported).⁶

LMWH is beneficial, but dosing can be tricky
Patients with a history of pregnancy-associated VTE—whether or not they have known thrombophilia—do benefit from routine ante- and postpartum thromboprophylaxis, per expert opinion in practice guidelines.^4,7,8 LMWH is the preferred agent because of its safety during pregnancy and ease of dosing.

Precise dosing is nonetheless difficult to determine because clinical studies in pregnant patients are lacking and renal clearance of LMWH increases during pregnancy. Most authors recommend doses between the prophylactic and therapeutic ranges.⁴ Subcutaneous enoxaparin, for example, can be given at 40 mg every 24 hours (more aggressive, thus higher-risk, dosing is as much as 1 mg/kg every 12 hours); dalteparin can be administered at 5000 units every 24 hours up to as much as 100 units/kg every 12 hours.⁹

Recommendations

The American College of Obstetricians and Gynecologists (ACOG) 2011 updated Practice Bulletin recommends thrombophilia testing for pregnant patients previously diagnosed with a pregnancy-associated VTE, although they acknowledge the lack of quality evidence to support this recommendation. ACOG also recommends ante- and postpartum thromboprophylaxis for such patients.⁹

The ACCP expert review recommends that all pregnant women diagnosed with VTE during a previous pregnancy wear graduated elastic compression stockings throughout pregnancy and for at least 6 weeks postpartum.⁷

The ACCP also recommends LMWH for all pregnant patients with a prior VTE. Additionally, the ACCP says that a thrombophilia work-up, while not routinely recommended, might be appropriate—contingent on additional risk assessment.⁷

Evidence summary

A population-based cohort study centered in Olmsted County, Minn (N=50,080 births between 1966 and 1995) established a baseline rate of VTE among pregnant patients (105 total events; 0.2% incidence), and found an increased relative risk of VTE among pregnant and postpartum patients (RR=4.29; 95% confidence interval [CI], 3.49-5.22; P<.001) compared with nonpregnant patients. The incidence of VTE was 199.7 per 100,000 woman-years. The postpartum annual incidence of VTE was 5 times higher than antepartum (511.2 vs 95.8 per 100,000).¹

Thrombophilia testing typically isn’t useful
There is no evidence of improved outcomes from screening pregnant women with prior VTEs for some of the more common hypercoagulable conditions, including factor V Leiden, prothrombin G20210A mutation, protein C and S deficiency, and antiphospholipid syndrome. A recent Clinical Inquiry addressed this question for general medical patients with idiopathic deep venous thrombosis and found no quality evidence to support a thrombophilia work-up in most patients.² A subsequent review, which addressed pregnant patients specifically, made the same recommendation, that is, no quality evidence supports a thrombophilia work-up in patients at risk for VTE.³

How effective is prophylactic anticoagulation?
A meta-analysis in the American College of Chest Physicians (ACCP) Evidence-Based Clinical Practice Guidelines reviewing data from 1953 orthopedic and medical patients who were mostly postoperative (and not including pregnant women) found that prophylactic anticoagulation with LMWH for patients at risk for VTE produced a relative risk for recurrent VTE of 0.36 (95% CI, 0.20-0.67).⁴

In a more recent prospective cohort study, prophylactic LMWH was given to 177 of 286 (62% treated) patients according to risk-based scoring for recurrent VTE.⁵ The treatment protocol called for anticoagulation antepartum, postpartum, or both, depending on risk score (the higher the risk, the longer the period of thromboprophylaxis). Patients with previous pregnancy-associated VTE received both antepartum and postpartum anticoagulation. The study found recurrent VTE rates of 0.35% (95% CI, 0-1.03) antepartum and 0.7% (95% CI, 0-1.67) postpartum among treated patients.⁵

Data from an earlier report summarized the expected VTE rate in patients not exposed to anticoagulation prophylaxis. This prospective cohort study evaluated 125 pregnant women with a history of prior VTE who had anticoagulation withheld and determined the rate of recurrent antepartum and postpartum VTE. Three women had an antepartum VTE (2.4%; 95% CI, 0.2-6.9). Three additional women developed postpartum VTE, for a total of 6 VTEs (4.8%, no CI reported).⁶

LMWH is beneficial, but dosing can be tricky
Patients with a history of pregnancy-associated VTE—whether or not they have known thrombophilia—do benefit from routine ante- and postpartum thromboprophylaxis, per expert opinion in practice guidelines.^4,7,8 LMWH is the preferred agent because of its safety during pregnancy and ease of dosing.

Precise dosing is nonetheless difficult to determine because clinical studies in pregnant patients are lacking and renal clearance of LMWH increases during pregnancy. Most authors recommend doses between the prophylactic and therapeutic ranges.⁴ Subcutaneous enoxaparin, for example, can be given at 40 mg every 24 hours (more aggressive, thus higher-risk, dosing is as much as 1 mg/kg every 12 hours); dalteparin can be administered at 5000 units every 24 hours up to as much as 100 units/kg every 12 hours.⁹

Recommendations

The American College of Obstetricians and Gynecologists (ACOG) 2011 updated Practice Bulletin recommends thrombophilia testing for pregnant patients previously diagnosed with a pregnancy-associated VTE, although they acknowledge the lack of quality evidence to support this recommendation. ACOG also recommends ante- and postpartum thromboprophylaxis for such patients.⁹

The ACCP expert review recommends that all pregnant women diagnosed with VTE during a previous pregnancy wear graduated elastic compression stockings throughout pregnancy and for at least 6 weeks postpartum.⁷

The ACCP also recommends LMWH for all pregnant patients with a prior VTE. Additionally, the ACCP says that a thrombophilia work-up, while not routinely recommended, might be appropriate—contingent on additional risk assessment.⁷

Evidence summary

The morning serum cortisol level is the most convenient test for adrenal insufficiency because it requires a single blood draw. The 250 mcg CST involves IV or IM administration of cosyntropin and several blood draws. The 1 mcg CST, introduced to improve detection of partial and secondary adrenal insufficiency, requires dilution of the cosyntropin before administration because the smallest available dose is 250 mcg.

The insulin tolerance test is widely considered the gold standard, but requires close observation, is unpleasant for the patient, and carries some risk. Metyrapone and corticotropin-releasing hormone tests are not widely available.¹

Negative CST rules out primary insufficiency

Researchers conducting a meta-analysis of the CST in diagnosing both primary and secondary adrenal insufficiency searched MEDLINE for English-language studies from 1966 to 2002 and used summary receiver-operating characteristic (ROC) curves to combine the sensitivities and specificities from individual studies.² Four studies of primary adrenal insufficiency showed a negative likelihood ratio of 0.026 for the 250 mcg CST. A negative CST would, therefore, significantly decrease the post-test probability of primary adrenal insufficiency and effectively rule out the condition.

However, primary adrenal insufficiency was already established in the 4 studies, and consecutive testing with an accepted gold standard was not done. Thus, the studies likely overestimate the accuracy of the CST test characteristics.

Using CST results for secondary insufficiency

Twenty studies evaluating the 250 mcg CST for diagnosing secondary adrenal insufficiency were of higher quality. They included patients with and without disease and compared the CST with gold-standard tests, either the insulin tolerance test or metyrapone test. The summary ROC curve indicated a negative likelihood ratio of 0.45, which would decrease only moderately the post-test probability of secondary adrenal insufficiency.

The 1 mcg CST: More discriminating than 250 mcg

Using a ROC curve generated from 22 studies, the authors found the test characteristics of the 250 mcg CST and the 1 mcg CST to be similar. Only 7 of these studies included paired data for the standard- and low-dose CST in the same patients, however. In the 7 studies with paired data, the 1 mcg CST had better diagnostic discrimination, based on a larger area under the ROC, than the 250 mcg CST.

13 mcg/dL is the rule-out threshold for morning serum cortisol

A subsequent meta-analysis, based on a PubMed search of English-language studies from 1966 to 2006, compared the performance of morning serum cortisol, the 1 mcg CST, and the 250 mcg CST for diagnosing secondary adrenal insufficiency. This analysis used patient-level data obtained from the original investigators instead of reported study-level results.³ Data from patients described as normal, healthy control subjects were excluded.

Studies included in the meta-analysis used an accepted gold-standard test, such as the insulin tolerance test or metyrapone test. Studies that were performed in a critical care setting or used older, less reliable cortisol assays were excluded, as were studies for which patient-level data couldn’t be obtained. Three new studies were included, and 12 of the previously used studies were excluded.

Instead of using the reported cortisol cutoff levels, the authors defined a negative test as the mean cortisol level (the “rule-out threshold”) above which the negative likelihood ratio of adrenal insufficiency is <0.15. The rule-out thresholds for morning serum cortisol, 1 mcg CST, and 250 mcg CST were 13, 22, and 30 mcg/dL, respectively.

An optimal testing strategy for secondary insufficiency

The authors proposed an optimal testing strategy for secondary adrenal insufficiency (assuming a low or moderate pretest probability) that starts with a morning serum cortisol measurement:

• A serum cortisol level >13 mcg/dL can effectively rule out adrenal insufficiency.
• If the morning serum cortisol is <13 mcg/dL, a 1 mcg CST >22 mcg/dL can rule out adrenal insufficiency.
• Patients would need an insulin tolerance test or metyrapone test only if the low-dose CST is <22 mcg/dL.

Recommendations

Williams Textbook of Endocrinology states that a basal cortisol level higher than 14.5 mcg/dL invariably indicates an intact hypothalamic-pituitary-adrenal axis. However, to confirm the diagnosis of adrenal insufficiency, all patients, except those with a recent pituitary insult, should undergo a CST. An insulin tolerance test should be done only if the patient has a subnormal response to cosyntropin (to rule out a false-positive CST) or has had a recent pituitary insult.⁴

Evidence summary

The morning serum cortisol level is the most convenient test for adrenal insufficiency because it requires a single blood draw. The 250 mcg CST involves IV or IM administration of cosyntropin and several blood draws. The 1 mcg CST, introduced to improve detection of partial and secondary adrenal insufficiency, requires dilution of the cosyntropin before administration because the smallest available dose is 250 mcg.

The insulin tolerance test is widely considered the gold standard, but requires close observation, is unpleasant for the patient, and carries some risk. Metyrapone and corticotropin-releasing hormone tests are not widely available.¹

Negative CST rules out primary insufficiency

Researchers conducting a meta-analysis of the CST in diagnosing both primary and secondary adrenal insufficiency searched MEDLINE for English-language studies from 1966 to 2002 and used summary receiver-operating characteristic (ROC) curves to combine the sensitivities and specificities from individual studies.² Four studies of primary adrenal insufficiency showed a negative likelihood ratio of 0.026 for the 250 mcg CST. A negative CST would, therefore, significantly decrease the post-test probability of primary adrenal insufficiency and effectively rule out the condition.

However, primary adrenal insufficiency was already established in the 4 studies, and consecutive testing with an accepted gold standard was not done. Thus, the studies likely overestimate the accuracy of the CST test characteristics.

Using CST results for secondary insufficiency

Twenty studies evaluating the 250 mcg CST for diagnosing secondary adrenal insufficiency were of higher quality. They included patients with and without disease and compared the CST with gold-standard tests, either the insulin tolerance test or metyrapone test. The summary ROC curve indicated a negative likelihood ratio of 0.45, which would decrease only moderately the post-test probability of secondary adrenal insufficiency.

The 1 mcg CST: More discriminating than 250 mcg

Using a ROC curve generated from 22 studies, the authors found the test characteristics of the 250 mcg CST and the 1 mcg CST to be similar. Only 7 of these studies included paired data for the standard- and low-dose CST in the same patients, however. In the 7 studies with paired data, the 1 mcg CST had better diagnostic discrimination, based on a larger area under the ROC, than the 250 mcg CST.

13 mcg/dL is the rule-out threshold for morning serum cortisol

A subsequent meta-analysis, based on a PubMed search of English-language studies from 1966 to 2006, compared the performance of morning serum cortisol, the 1 mcg CST, and the 250 mcg CST for diagnosing secondary adrenal insufficiency. This analysis used patient-level data obtained from the original investigators instead of reported study-level results.³ Data from patients described as normal, healthy control subjects were excluded.

Studies included in the meta-analysis used an accepted gold-standard test, such as the insulin tolerance test or metyrapone test. Studies that were performed in a critical care setting or used older, less reliable cortisol assays were excluded, as were studies for which patient-level data couldn’t be obtained. Three new studies were included, and 12 of the previously used studies were excluded.

Instead of using the reported cortisol cutoff levels, the authors defined a negative test as the mean cortisol level (the “rule-out threshold”) above which the negative likelihood ratio of adrenal insufficiency is <0.15. The rule-out thresholds for morning serum cortisol, 1 mcg CST, and 250 mcg CST were 13, 22, and 30 mcg/dL, respectively.

An optimal testing strategy for secondary insufficiency

The authors proposed an optimal testing strategy for secondary adrenal insufficiency (assuming a low or moderate pretest probability) that starts with a morning serum cortisol measurement:

• A serum cortisol level >13 mcg/dL can effectively rule out adrenal insufficiency.
• If the morning serum cortisol is <13 mcg/dL, a 1 mcg CST >22 mcg/dL can rule out adrenal insufficiency.
• Patients would need an insulin tolerance test or metyrapone test only if the low-dose CST is <22 mcg/dL.

Recommendations

Williams Textbook of Endocrinology states that a basal cortisol level higher than 14.5 mcg/dL invariably indicates an intact hypothalamic-pituitary-adrenal axis. However, to confirm the diagnosis of adrenal insufficiency, all patients, except those with a recent pituitary insult, should undergo a CST. An insulin tolerance test should be done only if the patient has a subnormal response to cosyntropin (to rule out a false-positive CST) or has had a recent pituitary insult.⁴

Evidence summary

The morning serum cortisol level is the most convenient test for adrenal insufficiency because it requires a single blood draw. The 250 mcg CST involves IV or IM administration of cosyntropin and several blood draws. The 1 mcg CST, introduced to improve detection of partial and secondary adrenal insufficiency, requires dilution of the cosyntropin before administration because the smallest available dose is 250 mcg.

The insulin tolerance test is widely considered the gold standard, but requires close observation, is unpleasant for the patient, and carries some risk. Metyrapone and corticotropin-releasing hormone tests are not widely available.¹

Negative CST rules out primary insufficiency

Researchers conducting a meta-analysis of the CST in diagnosing both primary and secondary adrenal insufficiency searched MEDLINE for English-language studies from 1966 to 2002 and used summary receiver-operating characteristic (ROC) curves to combine the sensitivities and specificities from individual studies.² Four studies of primary adrenal insufficiency showed a negative likelihood ratio of 0.026 for the 250 mcg CST. A negative CST would, therefore, significantly decrease the post-test probability of primary adrenal insufficiency and effectively rule out the condition.

However, primary adrenal insufficiency was already established in the 4 studies, and consecutive testing with an accepted gold standard was not done. Thus, the studies likely overestimate the accuracy of the CST test characteristics.

Using CST results for secondary insufficiency

Twenty studies evaluating the 250 mcg CST for diagnosing secondary adrenal insufficiency were of higher quality. They included patients with and without disease and compared the CST with gold-standard tests, either the insulin tolerance test or metyrapone test. The summary ROC curve indicated a negative likelihood ratio of 0.45, which would decrease only moderately the post-test probability of secondary adrenal insufficiency.

The 1 mcg CST: More discriminating than 250 mcg

Using a ROC curve generated from 22 studies, the authors found the test characteristics of the 250 mcg CST and the 1 mcg CST to be similar. Only 7 of these studies included paired data for the standard- and low-dose CST in the same patients, however. In the 7 studies with paired data, the 1 mcg CST had better diagnostic discrimination, based on a larger area under the ROC, than the 250 mcg CST.

13 mcg/dL is the rule-out threshold for morning serum cortisol

A subsequent meta-analysis, based on a PubMed search of English-language studies from 1966 to 2006, compared the performance of morning serum cortisol, the 1 mcg CST, and the 250 mcg CST for diagnosing secondary adrenal insufficiency. This analysis used patient-level data obtained from the original investigators instead of reported study-level results.³ Data from patients described as normal, healthy control subjects were excluded.

Studies included in the meta-analysis used an accepted gold-standard test, such as the insulin tolerance test or metyrapone test. Studies that were performed in a critical care setting or used older, less reliable cortisol assays were excluded, as were studies for which patient-level data couldn’t be obtained. Three new studies were included, and 12 of the previously used studies were excluded.

Instead of using the reported cortisol cutoff levels, the authors defined a negative test as the mean cortisol level (the “rule-out threshold”) above which the negative likelihood ratio of adrenal insufficiency is <0.15. The rule-out thresholds for morning serum cortisol, 1 mcg CST, and 250 mcg CST were 13, 22, and 30 mcg/dL, respectively.

An optimal testing strategy for secondary insufficiency

The authors proposed an optimal testing strategy for secondary adrenal insufficiency (assuming a low or moderate pretest probability) that starts with a morning serum cortisol measurement:

• A serum cortisol level >13 mcg/dL can effectively rule out adrenal insufficiency.
• If the morning serum cortisol is <13 mcg/dL, a 1 mcg CST >22 mcg/dL can rule out adrenal insufficiency.
• Patients would need an insulin tolerance test or metyrapone test only if the low-dose CST is <22 mcg/dL.

Recommendations

Williams Textbook of Endocrinology states that a basal cortisol level higher than 14.5 mcg/dL invariably indicates an intact hypothalamic-pituitary-adrenal axis. However, to confirm the diagnosis of adrenal insufficiency, all patients, except those with a recent pituitary insult, should undergo a CST. An insulin tolerance test should be done only if the patient has a subnormal response to cosyntropin (to rule out a false-positive CST) or has had a recent pituitary insult.⁴