A 21-year-old woman who is 12 weeks pregnant according to the date of her last menstrual period comes to the emergency department with shortness of breath and chest pain.

One week ago she began experiencing pre-syncope and shortness of breath on minimal exertion and then even at rest on most days. The shortness of breath worsened throughout the week, eventually limiting her daily activities to such a degree that she restricted herself to bed rest.

Her chest pain started today while she was sitting in church, without any apparent provocation. It is right-sided, sharp, and focal, and it does not radiate. At the same time, her shortness of breath was more severe than before, so she immediately came to the emergency department.

This is her third pregnancy; she has had one live birth and one abortion. Her last pregnancy was full-term, with routine prenatal care and no complications. However, so far during this pregnancy, she has had no prenatal care, she has not taken prenatal vitamins, and she has been unable to maintain adequate nutrition because of persistent emesis, which began early in her pregnancy and continues to occur as often as two or three times daily. She has lost 20 pounds over the past 12 weeks.

She says she has no close contacts who are sick, and she has had no fever, diarrhea, dysuria, urinary frequency or urgency, palpitations, swelling of the legs or feet, blurry vision, or increase in neck girth. She says she does not smoke or use alcohol or illicit substances. Her only previous surgery was laser-assisted in situ keratoplasty (LASIK) eye surgery in 1998. She is allergic to seafood only. She has not eaten at any new places recently. She is up to date with her childhood vaccinations. She has no family history of hypercoagulability or venous thrombotic events.

PHYSICAL EXAMINATION

She is breathing rapidly—as fast as 45 breaths per minute. Her temperature is 37.2°C (98.9°F), blood pressure 95/60 mm Hg, oxygen saturation 100% while on 10 L of oxygen using a nonrebreather mask, pulse 102 beats per minute, and weight 55.9 kg (123.2 pounds). She appears alert, oriented, and comfortable, with a thin body habitus. She has no jugular venous distention, neck mass, or thyromegaly. Her lungs are clear to auscultation, with no wheezes or rales. The cardiovascular examination is normal. She has a regular heart rate and rhythm, normal S1 and S2 sounds, and no rubs, clicks, or murmurs. Pulses in the extremities are normal, and she has no peripheral edema. The neurologic examination is normal.

Electrocardiography shows sinus tachycardia with first-degree atrioventricular block.

DIFFERENTIAL DIAGNOSIS

1. At this point, which is the most probable cause of her symptoms?

• Pulmonary embolism
• Peripartum cardiomyopathy
• Acute coronary syndrome
• Aortic dissection
• Expected physiologic changes of pregnancy

Pulmonary embolism would be the most probable diagnosis, given the patient’s pregnancy, shortness of breath, and tachycardia and the pleuritic quality of her chest pain.

Peripartum cardiomyopathy is also a possible cause, as it may present with profound shortness of breath and markedly decreased cardiac function. But it is much less likely in this patient because she is early in her pregnancy, and peripartum cardiomyopathy usually is seen during the last month of gestation or the first months after delivery.

Acute coronary syndrome is unlikely, given her young age and the lack of significant risk factors or a supporting history.

Aortic dissection is unlikely in view of her medical history.

Physiologic changes of pregnancy. Many pregnant women experience a sensation of not being able to catch their breath or expand their lungs fully, as the diaphragm is limited by the gravid abdomen. They also present with dyspnea, fatigue, reduced exercise capacity, peripheral edema, or volume overload.¹ However, these changes tend to occur gradually and worsen over time. This patient’s degree of shortness of breath and its sudden onset do not seem like normal physiologic changes of pregnancy.

Other possible causes of dyspnea in a pregnant woman include asthma, pleural empyema, pneumonia, and severe anemia. Asthma should be considered in anyone with a history of wheezing, cough, and dyspnea. Fever and sputum production would support a diagnosis of pneumonia or empyema. In addition, maternal heart disease (eg, endocarditis, pulmonary hypertension) complicates 0.2% to 3% of pregnancies.¹

CASE CONTINUED

The emergency department staff decide to evaluate the patient for heart failure and pulmonary embolism.

Bedside echocardiography reveals an ejection fraction of 55% (normal range 50%–75%), normal heart function and size, and no valvular abnormalities.

Chest radiography is normal.

Lower-extremity duplex ultrasonography is negative for deep-vein thrombosis.

The D-dimer level is 380 ng/mL (normal range < 500 ng/mL).

The medical intensive care unit is consulted about the patient’s continued tachypnea and the possible need for intubation. A ventilation-perfusion scan is performed to screen for pulmonary embolism, and it is negative.

An obstetric team performs Doppler ultrasonography at the bedside; a fetal heartbeat can be heard, thus confirming a viable pregnancy.

The patient has normal serum levels of the cardiac enzymes troponin T and creatine kinase-MB fraction, thus all but ruling out myocardial ischemia.

The patient is admitted to the hospital the next day, and a cardiology consult is obtained.

RULING OUT PULMONARY EMBOLISM

2. Has pulmonary embolism been definitively ruled out at this point?

• Yes
• No

The answer is no. The negative ventilation-perfusion scan and normal D-dimer test in this patient are not enough to rule out pulmonary embolism. The diagnosis of pulmonary embolism should be based on the clinician’s estimation of the pretest probability of pulmonary embolism (which is based on presenting signs and symptoms), as well as on a variety of tests, including spiral computed tomography (CT), ventilation-perfusion lung scanning, and serum D-dimer testing. Signs and symptoms that may guide the clinician are chest pain (present in 70% of patients with pulmonary embolism), tachypnea (70%), cough (40%), shortness of breath (25%), and tachycardia (33%).² A history of pregnancy, malignancy, immobility, or recent surgery may also increase the pretest probability of pulmonary embolism. In many cases, one’s clinical suspicion is highly predictive and is useful in diagnosing pulmonary embolism.

The accuracy of the tests varies widely, depending on the pretest probability of pulmonary embolism. For instance, in a patient with a high pretest probability but a low-probability ventilation-perfusion scan, the true probability of pulmonary embolism is 40%, but in a patient with a low pretest probability and a low-probability scan, the probability is only 4%.

The Wells criteria can be used to calculate the pretest probability of pulmonary embolism. Given this patient’s tachycardia and clinical presentation, her pretest probability according to the Wells criteria indicates increased risk. However, because her D-dimer test, lower-extremity Doppler test, and ventilation-perfusion scan were normal, pulmonary embolism is less likely.³

However, if one’s clinical suspicion is high enough, further investigation of pulmonary embolism would proceed despite the encouraging test results.

CASE CONTINUED

The cardiology consult team notes that her beta human chorionic gonadotropin (beta-hCG) level is much higher than would be expected at 12 weeks of pregnancy, and so they are concerned about the possibility of a molar pregnancy. In addition, her level of thyroid-stimulating hormone (TSH, or thyrotropin) is markedly low.

HYPERTHYROIDISM IN PREGNANCY

3. Which of the following would not explain this patient’s markedly low TSH level?

• Graves disease
• Molar pregnancy
• TSH-secreting pituitary adenoma
• Gestational transient thyrotoxicosis
• Twin pregnancy

Hyperthyroidism (also called thyrotoxicosis) has many causes, including but not limited to Graves disease, pituitary adenoma, struma ovarii (teratoma), hCG-secreting hydatidiform mole, and thyroid carcinoma (which is rare).⁴ In most of these disorders, the TSH level is low while the levels of thyroxine (T₄), triiodothyronine (T₃), or both are high.

Symptoms of hyperthyroidism are the effect of elevated T₄ and T₃ levels on the target organs themselves. Common symptoms include fever, tachycardia, tremor, stare, sweating, and lid lag. Other symptoms include nervousness, delirium, hypersensitivity to heat, flushing, palpitations, fatigue, weight loss, dyspnea, weakness, increased appetite, swelling of the legs, nausea, vomiting, diarrhea, goiter, tremor, atrial fibrillation, and cardiac failure.⁴ In its extreme form, called thyroid storm, thyrotoxicosis can be life-threatening. The likelihood of an impending thyroid storm can be assessed by clinical variables such as the patient’s temperature and heart rate and whether he or she has heart failure or gastrointestinal manifestations.⁵

Graves disease, the most common cause of hyperthyroidism in pregnancy, is due to stimulation of TSH receptors by antibodies against these receptors. Graves disease is possible in this patient, but a subsequent TSH receptor antibody test is negative.

Pituitary adenomas are one of the few causes of hyperthyroidism in which the TSH level is high, not low. Therefore, this is the correct answer.

Gestational transient thyrotoxicosis is a nonautoimmune condition that results in transient hyperthyroidism of variable severity.⁶ Usually, it occurs in otherwise normal pregnancies without complications, but the initial manifestation is hyper- emesis.⁶ It can be differentiated from Graves disease by the absence of TSH receptor antibodies and by no history of thyroid disorder.⁷ Common symptoms of gestational transient thyrotoxicosis include weight loss (or failure to gain weight), tachycardia, and fatigue.

The reason for the transient rise in ^T4 may be that beta-hCG is structurally similar to TSH (and also to luteinizing hormone and follicle-stimulating hormone), so that it has mild thyroid-stimulating effects.⁷ Sustained high levels of beta-hCG may in time give rise to the manifestations of thyrotoxicosis.

Molar pregnancy also can cause hyper-thyroidism via elevated levels of beta-hCG. However, twin pregnancy is more common and can produce sustained levels of beta-hCG above 100,000 IU/L. In most cases of twin pregnancy, the TSH level is decreased and the T₄ level transiently elevated.⁶ The elevated beta-hCG and the subsequent thyrotropic manifestations are thought to be directly related, and symptoms resolve when beta-hCG levels go down.⁶

In most cases of hyperthyroidism in pregnancy, the acute condition can be managed by a short (≤ 2-month) course of a beta-blocker. In rare cases, propylthiouracil treatment may be required. Gestational transient thyrotoxicosis is not associated with detrimental outcomes.

Case continued

Our patient’s TSH level is low and her free T₄ and T₃ levels are elevated. Her high beta-hCG level may be stimulating the thyroid gland and may account for the low TSH value, as well as for her tachycardia, emesis, shortness of breath, and weight loss.

After an obstetric consult, it is determined that our patient has a viable pregnancy. However, further investigation with transvaginal ultrasonography reveals that she has two viable, single-placenta, intrauterine gestations, separated by a thin chorionic membrane.

Beta-hCG and free T₄ levels are significantly higher in twin pregnancies than in single pregnancies, especially in the early stages.⁶ In our patient, the twin pregnancy led to the elevated beta-hCG, which eventually manifested as thyrotoxicosis, which caused the shortness of breath, hyperemesis, weight loss, tachycardia, and nausea.

Shortness of breath in patients with thyrotoxicosis is well recognized but not well explained. It may be caused by decreased lung compliance, engorged capillaries in the lung, or left ventricular failure, as well as by chest pain due to increased myocardial demand or coronary artery vasospasm.⁴ The dyspnea is present at rest and during exertion, and the high metabolic rate is thought to lead to an inappropriate response of the ventilatory system.^3,8

WHAT TREATMENT?

4. How would you treat this patient at this point?

• No drug therapy, just supportive care
• Propranolol (Inderal)
• Levothyroxine
• Propylthiouracil

Several types of drugs are used to manage hyperthyroidism.

Antithyroid drugs such as propylthiouracil, methimazole (Northyx, Tapazole), and carbimazole block thyroid hormone synthesis by inhibiting thyroid peroxidase. Propylthiouracil also blocks peripheral conversion of T₄ to T₃. Side effects of these agents include abnormal sense of taste, pruritus, urticaria, agranulocytosis, and hepatotoxicity.⁴

Usually, hyperthyroidism is treated with propylthiouracil at the smallest effective dose. This has been proven to be safe to the fetus and mother during pregnancy.⁹ Propylthiouracil and the other drugs in its class cross the placenta, but propylthiouracil crosses at one-quarter the rate of the other two.⁹

Beta-blockers are effective in the acute phase of thyrotoxicosis against tachycardia, hypertension, and atrial fibrillation. They also decrease conversion of T₄ to T₃, which is an added benefit. Beta-blockers can be tapered as thyroid hormone levels decrease.

A short course of a short-acting beta-blocker would be an option for our patient and would decrease her symptoms, although she does not have the typical markedly elevated T₄ or T₃ levels. In the long term, a beta-blocker would present a fetal risk, but short courses can be tolerated without incident.⁹

Radioactive iodine 131 is used in patients with Graves disease. ¹³¹Iodine therapy is safe for most adults, but in pregnancy its use is contraindicated. Fetal thyroid tissue is thought to be present after 10 weeks of gestation and could be damaged by the use of radioactive iodine. Another warning with the use of radioactive iodine is that patients should avoid close contact with other adults for a few days after treatment, and should avoid close contact with children and pregnant women for 2 to 3 weeks after treatment because of the risk of exposure to radiation emanating from the thyroid gland.

Levothyroxine is a treatment for hypothyroidism, not hyperthyroidism.

CASE CONTINUED

Our patient is treated with propranolol and monitored for several days in the hospital, during which her symptoms markedly improve. She is discharged without complications.

TAKE-HOME POINTS

The evaluation of shortness of breath in adult patients can be difficult, given the many possible causes. It is especially challenging in pregnant patients, since normal physiologic changes of pregnancy may produce these symptoms.

In many instances, cardiomyopathy must be suspected if a pregnant patient complains of shortness of breath. However, it is not the only possible cause.

A 21-year-old woman who is 12 weeks pregnant according to the date of her last menstrual period comes to the emergency department with shortness of breath and chest pain.

One week ago she began experiencing pre-syncope and shortness of breath on minimal exertion and then even at rest on most days. The shortness of breath worsened throughout the week, eventually limiting her daily activities to such a degree that she restricted herself to bed rest.

Her chest pain started today while she was sitting in church, without any apparent provocation. It is right-sided, sharp, and focal, and it does not radiate. At the same time, her shortness of breath was more severe than before, so she immediately came to the emergency department.

This is her third pregnancy; she has had one live birth and one abortion. Her last pregnancy was full-term, with routine prenatal care and no complications. However, so far during this pregnancy, she has had no prenatal care, she has not taken prenatal vitamins, and she has been unable to maintain adequate nutrition because of persistent emesis, which began early in her pregnancy and continues to occur as often as two or three times daily. She has lost 20 pounds over the past 12 weeks.

She says she has no close contacts who are sick, and she has had no fever, diarrhea, dysuria, urinary frequency or urgency, palpitations, swelling of the legs or feet, blurry vision, or increase in neck girth. She says she does not smoke or use alcohol or illicit substances. Her only previous surgery was laser-assisted in situ keratoplasty (LASIK) eye surgery in 1998. She is allergic to seafood only. She has not eaten at any new places recently. She is up to date with her childhood vaccinations. She has no family history of hypercoagulability or venous thrombotic events.

PHYSICAL EXAMINATION

She is breathing rapidly—as fast as 45 breaths per minute. Her temperature is 37.2°C (98.9°F), blood pressure 95/60 mm Hg, oxygen saturation 100% while on 10 L of oxygen using a nonrebreather mask, pulse 102 beats per minute, and weight 55.9 kg (123.2 pounds). She appears alert, oriented, and comfortable, with a thin body habitus. She has no jugular venous distention, neck mass, or thyromegaly. Her lungs are clear to auscultation, with no wheezes or rales. The cardiovascular examination is normal. She has a regular heart rate and rhythm, normal S1 and S2 sounds, and no rubs, clicks, or murmurs. Pulses in the extremities are normal, and she has no peripheral edema. The neurologic examination is normal.

Electrocardiography shows sinus tachycardia with first-degree atrioventricular block.

DIFFERENTIAL DIAGNOSIS

1. At this point, which is the most probable cause of her symptoms?

• Pulmonary embolism
• Peripartum cardiomyopathy
• Acute coronary syndrome
• Aortic dissection
• Expected physiologic changes of pregnancy

Pulmonary embolism would be the most probable diagnosis, given the patient’s pregnancy, shortness of breath, and tachycardia and the pleuritic quality of her chest pain.

Peripartum cardiomyopathy is also a possible cause, as it may present with profound shortness of breath and markedly decreased cardiac function. But it is much less likely in this patient because she is early in her pregnancy, and peripartum cardiomyopathy usually is seen during the last month of gestation or the first months after delivery.

Acute coronary syndrome is unlikely, given her young age and the lack of significant risk factors or a supporting history.

Aortic dissection is unlikely in view of her medical history.

Physiologic changes of pregnancy. Many pregnant women experience a sensation of not being able to catch their breath or expand their lungs fully, as the diaphragm is limited by the gravid abdomen. They also present with dyspnea, fatigue, reduced exercise capacity, peripheral edema, or volume overload.¹ However, these changes tend to occur gradually and worsen over time. This patient’s degree of shortness of breath and its sudden onset do not seem like normal physiologic changes of pregnancy.

Other possible causes of dyspnea in a pregnant woman include asthma, pleural empyema, pneumonia, and severe anemia. Asthma should be considered in anyone with a history of wheezing, cough, and dyspnea. Fever and sputum production would support a diagnosis of pneumonia or empyema. In addition, maternal heart disease (eg, endocarditis, pulmonary hypertension) complicates 0.2% to 3% of pregnancies.¹

CASE CONTINUED

The emergency department staff decide to evaluate the patient for heart failure and pulmonary embolism.

Bedside echocardiography reveals an ejection fraction of 55% (normal range 50%–75%), normal heart function and size, and no valvular abnormalities.

Chest radiography is normal.

Lower-extremity duplex ultrasonography is negative for deep-vein thrombosis.

The D-dimer level is 380 ng/mL (normal range < 500 ng/mL).

The medical intensive care unit is consulted about the patient’s continued tachypnea and the possible need for intubation. A ventilation-perfusion scan is performed to screen for pulmonary embolism, and it is negative.

An obstetric team performs Doppler ultrasonography at the bedside; a fetal heartbeat can be heard, thus confirming a viable pregnancy.

The patient has normal serum levels of the cardiac enzymes troponin T and creatine kinase-MB fraction, thus all but ruling out myocardial ischemia.

The patient is admitted to the hospital the next day, and a cardiology consult is obtained.

RULING OUT PULMONARY EMBOLISM

2. Has pulmonary embolism been definitively ruled out at this point?

• Yes
• No

The answer is no. The negative ventilation-perfusion scan and normal D-dimer test in this patient are not enough to rule out pulmonary embolism. The diagnosis of pulmonary embolism should be based on the clinician’s estimation of the pretest probability of pulmonary embolism (which is based on presenting signs and symptoms), as well as on a variety of tests, including spiral computed tomography (CT), ventilation-perfusion lung scanning, and serum D-dimer testing. Signs and symptoms that may guide the clinician are chest pain (present in 70% of patients with pulmonary embolism), tachypnea (70%), cough (40%), shortness of breath (25%), and tachycardia (33%).² A history of pregnancy, malignancy, immobility, or recent surgery may also increase the pretest probability of pulmonary embolism. In many cases, one’s clinical suspicion is highly predictive and is useful in diagnosing pulmonary embolism.

The accuracy of the tests varies widely, depending on the pretest probability of pulmonary embolism. For instance, in a patient with a high pretest probability but a low-probability ventilation-perfusion scan, the true probability of pulmonary embolism is 40%, but in a patient with a low pretest probability and a low-probability scan, the probability is only 4%.

The Wells criteria can be used to calculate the pretest probability of pulmonary embolism. Given this patient’s tachycardia and clinical presentation, her pretest probability according to the Wells criteria indicates increased risk. However, because her D-dimer test, lower-extremity Doppler test, and ventilation-perfusion scan were normal, pulmonary embolism is less likely.³

However, if one’s clinical suspicion is high enough, further investigation of pulmonary embolism would proceed despite the encouraging test results.

CASE CONTINUED

The cardiology consult team notes that her beta human chorionic gonadotropin (beta-hCG) level is much higher than would be expected at 12 weeks of pregnancy, and so they are concerned about the possibility of a molar pregnancy. In addition, her level of thyroid-stimulating hormone (TSH, or thyrotropin) is markedly low.

HYPERTHYROIDISM IN PREGNANCY

3. Which of the following would not explain this patient’s markedly low TSH level?

• Graves disease
• Molar pregnancy
• TSH-secreting pituitary adenoma
• Gestational transient thyrotoxicosis
• Twin pregnancy

Hyperthyroidism (also called thyrotoxicosis) has many causes, including but not limited to Graves disease, pituitary adenoma, struma ovarii (teratoma), hCG-secreting hydatidiform mole, and thyroid carcinoma (which is rare).⁴ In most of these disorders, the TSH level is low while the levels of thyroxine (T₄), triiodothyronine (T₃), or both are high.

Symptoms of hyperthyroidism are the effect of elevated T₄ and T₃ levels on the target organs themselves. Common symptoms include fever, tachycardia, tremor, stare, sweating, and lid lag. Other symptoms include nervousness, delirium, hypersensitivity to heat, flushing, palpitations, fatigue, weight loss, dyspnea, weakness, increased appetite, swelling of the legs, nausea, vomiting, diarrhea, goiter, tremor, atrial fibrillation, and cardiac failure.⁴ In its extreme form, called thyroid storm, thyrotoxicosis can be life-threatening. The likelihood of an impending thyroid storm can be assessed by clinical variables such as the patient’s temperature and heart rate and whether he or she has heart failure or gastrointestinal manifestations.⁵

Graves disease, the most common cause of hyperthyroidism in pregnancy, is due to stimulation of TSH receptors by antibodies against these receptors. Graves disease is possible in this patient, but a subsequent TSH receptor antibody test is negative.

Pituitary adenomas are one of the few causes of hyperthyroidism in which the TSH level is high, not low. Therefore, this is the correct answer.

Gestational transient thyrotoxicosis is a nonautoimmune condition that results in transient hyperthyroidism of variable severity.⁶ Usually, it occurs in otherwise normal pregnancies without complications, but the initial manifestation is hyper- emesis.⁶ It can be differentiated from Graves disease by the absence of TSH receptor antibodies and by no history of thyroid disorder.⁷ Common symptoms of gestational transient thyrotoxicosis include weight loss (or failure to gain weight), tachycardia, and fatigue.

The reason for the transient rise in ^T4 may be that beta-hCG is structurally similar to TSH (and also to luteinizing hormone and follicle-stimulating hormone), so that it has mild thyroid-stimulating effects.⁷ Sustained high levels of beta-hCG may in time give rise to the manifestations of thyrotoxicosis.

Molar pregnancy also can cause hyper-thyroidism via elevated levels of beta-hCG. However, twin pregnancy is more common and can produce sustained levels of beta-hCG above 100,000 IU/L. In most cases of twin pregnancy, the TSH level is decreased and the T₄ level transiently elevated.⁶ The elevated beta-hCG and the subsequent thyrotropic manifestations are thought to be directly related, and symptoms resolve when beta-hCG levels go down.⁶

In most cases of hyperthyroidism in pregnancy, the acute condition can be managed by a short (≤ 2-month) course of a beta-blocker. In rare cases, propylthiouracil treatment may be required. Gestational transient thyrotoxicosis is not associated with detrimental outcomes.

Case continued

Our patient’s TSH level is low and her free T₄ and T₃ levels are elevated. Her high beta-hCG level may be stimulating the thyroid gland and may account for the low TSH value, as well as for her tachycardia, emesis, shortness of breath, and weight loss.

After an obstetric consult, it is determined that our patient has a viable pregnancy. However, further investigation with transvaginal ultrasonography reveals that she has two viable, single-placenta, intrauterine gestations, separated by a thin chorionic membrane.

Beta-hCG and free T₄ levels are significantly higher in twin pregnancies than in single pregnancies, especially in the early stages.⁶ In our patient, the twin pregnancy led to the elevated beta-hCG, which eventually manifested as thyrotoxicosis, which caused the shortness of breath, hyperemesis, weight loss, tachycardia, and nausea.

Shortness of breath in patients with thyrotoxicosis is well recognized but not well explained. It may be caused by decreased lung compliance, engorged capillaries in the lung, or left ventricular failure, as well as by chest pain due to increased myocardial demand or coronary artery vasospasm.⁴ The dyspnea is present at rest and during exertion, and the high metabolic rate is thought to lead to an inappropriate response of the ventilatory system.^3,8

WHAT TREATMENT?

4. How would you treat this patient at this point?

• No drug therapy, just supportive care
• Propranolol (Inderal)
• Levothyroxine
• Propylthiouracil

Several types of drugs are used to manage hyperthyroidism.

Antithyroid drugs such as propylthiouracil, methimazole (Northyx, Tapazole), and carbimazole block thyroid hormone synthesis by inhibiting thyroid peroxidase. Propylthiouracil also blocks peripheral conversion of T₄ to T₃. Side effects of these agents include abnormal sense of taste, pruritus, urticaria, agranulocytosis, and hepatotoxicity.⁴

Usually, hyperthyroidism is treated with propylthiouracil at the smallest effective dose. This has been proven to be safe to the fetus and mother during pregnancy.⁹ Propylthiouracil and the other drugs in its class cross the placenta, but propylthiouracil crosses at one-quarter the rate of the other two.⁹

Beta-blockers are effective in the acute phase of thyrotoxicosis against tachycardia, hypertension, and atrial fibrillation. They also decrease conversion of T₄ to T₃, which is an added benefit. Beta-blockers can be tapered as thyroid hormone levels decrease.

A short course of a short-acting beta-blocker would be an option for our patient and would decrease her symptoms, although she does not have the typical markedly elevated T₄ or T₃ levels. In the long term, a beta-blocker would present a fetal risk, but short courses can be tolerated without incident.⁹

Radioactive iodine 131 is used in patients with Graves disease. ¹³¹Iodine therapy is safe for most adults, but in pregnancy its use is contraindicated. Fetal thyroid tissue is thought to be present after 10 weeks of gestation and could be damaged by the use of radioactive iodine. Another warning with the use of radioactive iodine is that patients should avoid close contact with other adults for a few days after treatment, and should avoid close contact with children and pregnant women for 2 to 3 weeks after treatment because of the risk of exposure to radiation emanating from the thyroid gland.

Levothyroxine is a treatment for hypothyroidism, not hyperthyroidism.

CASE CONTINUED

Our patient is treated with propranolol and monitored for several days in the hospital, during which her symptoms markedly improve. She is discharged without complications.

TAKE-HOME POINTS

The evaluation of shortness of breath in adult patients can be difficult, given the many possible causes. It is especially challenging in pregnant patients, since normal physiologic changes of pregnancy may produce these symptoms.

In many instances, cardiomyopathy must be suspected if a pregnant patient complains of shortness of breath. However, it is not the only possible cause.

A 21-year-old woman who is 12 weeks pregnant according to the date of her last menstrual period comes to the emergency department with shortness of breath and chest pain.

One week ago she began experiencing pre-syncope and shortness of breath on minimal exertion and then even at rest on most days. The shortness of breath worsened throughout the week, eventually limiting her daily activities to such a degree that she restricted herself to bed rest.

Her chest pain started today while she was sitting in church, without any apparent provocation. It is right-sided, sharp, and focal, and it does not radiate. At the same time, her shortness of breath was more severe than before, so she immediately came to the emergency department.

This is her third pregnancy; she has had one live birth and one abortion. Her last pregnancy was full-term, with routine prenatal care and no complications. However, so far during this pregnancy, she has had no prenatal care, she has not taken prenatal vitamins, and she has been unable to maintain adequate nutrition because of persistent emesis, which began early in her pregnancy and continues to occur as often as two or three times daily. She has lost 20 pounds over the past 12 weeks.

She says she has no close contacts who are sick, and she has had no fever, diarrhea, dysuria, urinary frequency or urgency, palpitations, swelling of the legs or feet, blurry vision, or increase in neck girth. She says she does not smoke or use alcohol or illicit substances. Her only previous surgery was laser-assisted in situ keratoplasty (LASIK) eye surgery in 1998. She is allergic to seafood only. She has not eaten at any new places recently. She is up to date with her childhood vaccinations. She has no family history of hypercoagulability or venous thrombotic events.

PHYSICAL EXAMINATION

She is breathing rapidly—as fast as 45 breaths per minute. Her temperature is 37.2°C (98.9°F), blood pressure 95/60 mm Hg, oxygen saturation 100% while on 10 L of oxygen using a nonrebreather mask, pulse 102 beats per minute, and weight 55.9 kg (123.2 pounds). She appears alert, oriented, and comfortable, with a thin body habitus. She has no jugular venous distention, neck mass, or thyromegaly. Her lungs are clear to auscultation, with no wheezes or rales. The cardiovascular examination is normal. She has a regular heart rate and rhythm, normal S1 and S2 sounds, and no rubs, clicks, or murmurs. Pulses in the extremities are normal, and she has no peripheral edema. The neurologic examination is normal.

Electrocardiography shows sinus tachycardia with first-degree atrioventricular block.

DIFFERENTIAL DIAGNOSIS

1. At this point, which is the most probable cause of her symptoms?

• Pulmonary embolism
• Peripartum cardiomyopathy
• Acute coronary syndrome
• Aortic dissection
• Expected physiologic changes of pregnancy

Pulmonary embolism would be the most probable diagnosis, given the patient’s pregnancy, shortness of breath, and tachycardia and the pleuritic quality of her chest pain.

Peripartum cardiomyopathy is also a possible cause, as it may present with profound shortness of breath and markedly decreased cardiac function. But it is much less likely in this patient because she is early in her pregnancy, and peripartum cardiomyopathy usually is seen during the last month of gestation or the first months after delivery.

Acute coronary syndrome is unlikely, given her young age and the lack of significant risk factors or a supporting history.

Aortic dissection is unlikely in view of her medical history.

Physiologic changes of pregnancy. Many pregnant women experience a sensation of not being able to catch their breath or expand their lungs fully, as the diaphragm is limited by the gravid abdomen. They also present with dyspnea, fatigue, reduced exercise capacity, peripheral edema, or volume overload.¹ However, these changes tend to occur gradually and worsen over time. This patient’s degree of shortness of breath and its sudden onset do not seem like normal physiologic changes of pregnancy.

Other possible causes of dyspnea in a pregnant woman include asthma, pleural empyema, pneumonia, and severe anemia. Asthma should be considered in anyone with a history of wheezing, cough, and dyspnea. Fever and sputum production would support a diagnosis of pneumonia or empyema. In addition, maternal heart disease (eg, endocarditis, pulmonary hypertension) complicates 0.2% to 3% of pregnancies.¹

CASE CONTINUED

The emergency department staff decide to evaluate the patient for heart failure and pulmonary embolism.

Bedside echocardiography reveals an ejection fraction of 55% (normal range 50%–75%), normal heart function and size, and no valvular abnormalities.

Chest radiography is normal.

Lower-extremity duplex ultrasonography is negative for deep-vein thrombosis.

The D-dimer level is 380 ng/mL (normal range < 500 ng/mL).

The medical intensive care unit is consulted about the patient’s continued tachypnea and the possible need for intubation. A ventilation-perfusion scan is performed to screen for pulmonary embolism, and it is negative.

An obstetric team performs Doppler ultrasonography at the bedside; a fetal heartbeat can be heard, thus confirming a viable pregnancy.

The patient has normal serum levels of the cardiac enzymes troponin T and creatine kinase-MB fraction, thus all but ruling out myocardial ischemia.

The patient is admitted to the hospital the next day, and a cardiology consult is obtained.

RULING OUT PULMONARY EMBOLISM

2. Has pulmonary embolism been definitively ruled out at this point?

• Yes
• No

The answer is no. The negative ventilation-perfusion scan and normal D-dimer test in this patient are not enough to rule out pulmonary embolism. The diagnosis of pulmonary embolism should be based on the clinician’s estimation of the pretest probability of pulmonary embolism (which is based on presenting signs and symptoms), as well as on a variety of tests, including spiral computed tomography (CT), ventilation-perfusion lung scanning, and serum D-dimer testing. Signs and symptoms that may guide the clinician are chest pain (present in 70% of patients with pulmonary embolism), tachypnea (70%), cough (40%), shortness of breath (25%), and tachycardia (33%).² A history of pregnancy, malignancy, immobility, or recent surgery may also increase the pretest probability of pulmonary embolism. In many cases, one’s clinical suspicion is highly predictive and is useful in diagnosing pulmonary embolism.

The accuracy of the tests varies widely, depending on the pretest probability of pulmonary embolism. For instance, in a patient with a high pretest probability but a low-probability ventilation-perfusion scan, the true probability of pulmonary embolism is 40%, but in a patient with a low pretest probability and a low-probability scan, the probability is only 4%.

The Wells criteria can be used to calculate the pretest probability of pulmonary embolism. Given this patient’s tachycardia and clinical presentation, her pretest probability according to the Wells criteria indicates increased risk. However, because her D-dimer test, lower-extremity Doppler test, and ventilation-perfusion scan were normal, pulmonary embolism is less likely.³

However, if one’s clinical suspicion is high enough, further investigation of pulmonary embolism would proceed despite the encouraging test results.

CASE CONTINUED

The cardiology consult team notes that her beta human chorionic gonadotropin (beta-hCG) level is much higher than would be expected at 12 weeks of pregnancy, and so they are concerned about the possibility of a molar pregnancy. In addition, her level of thyroid-stimulating hormone (TSH, or thyrotropin) is markedly low.

HYPERTHYROIDISM IN PREGNANCY

3. Which of the following would not explain this patient’s markedly low TSH level?

• Graves disease
• Molar pregnancy
• TSH-secreting pituitary adenoma
• Gestational transient thyrotoxicosis
• Twin pregnancy

Hyperthyroidism (also called thyrotoxicosis) has many causes, including but not limited to Graves disease, pituitary adenoma, struma ovarii (teratoma), hCG-secreting hydatidiform mole, and thyroid carcinoma (which is rare).⁴ In most of these disorders, the TSH level is low while the levels of thyroxine (T₄), triiodothyronine (T₃), or both are high.

Symptoms of hyperthyroidism are the effect of elevated T₄ and T₃ levels on the target organs themselves. Common symptoms include fever, tachycardia, tremor, stare, sweating, and lid lag. Other symptoms include nervousness, delirium, hypersensitivity to heat, flushing, palpitations, fatigue, weight loss, dyspnea, weakness, increased appetite, swelling of the legs, nausea, vomiting, diarrhea, goiter, tremor, atrial fibrillation, and cardiac failure.⁴ In its extreme form, called thyroid storm, thyrotoxicosis can be life-threatening. The likelihood of an impending thyroid storm can be assessed by clinical variables such as the patient’s temperature and heart rate and whether he or she has heart failure or gastrointestinal manifestations.⁵

Graves disease, the most common cause of hyperthyroidism in pregnancy, is due to stimulation of TSH receptors by antibodies against these receptors. Graves disease is possible in this patient, but a subsequent TSH receptor antibody test is negative.

Pituitary adenomas are one of the few causes of hyperthyroidism in which the TSH level is high, not low. Therefore, this is the correct answer.

Gestational transient thyrotoxicosis is a nonautoimmune condition that results in transient hyperthyroidism of variable severity.⁶ Usually, it occurs in otherwise normal pregnancies without complications, but the initial manifestation is hyper- emesis.⁶ It can be differentiated from Graves disease by the absence of TSH receptor antibodies and by no history of thyroid disorder.⁷ Common symptoms of gestational transient thyrotoxicosis include weight loss (or failure to gain weight), tachycardia, and fatigue.

The reason for the transient rise in ^T4 may be that beta-hCG is structurally similar to TSH (and also to luteinizing hormone and follicle-stimulating hormone), so that it has mild thyroid-stimulating effects.⁷ Sustained high levels of beta-hCG may in time give rise to the manifestations of thyrotoxicosis.

Molar pregnancy also can cause hyper-thyroidism via elevated levels of beta-hCG. However, twin pregnancy is more common and can produce sustained levels of beta-hCG above 100,000 IU/L. In most cases of twin pregnancy, the TSH level is decreased and the T₄ level transiently elevated.⁶ The elevated beta-hCG and the subsequent thyrotropic manifestations are thought to be directly related, and symptoms resolve when beta-hCG levels go down.⁶

In most cases of hyperthyroidism in pregnancy, the acute condition can be managed by a short (≤ 2-month) course of a beta-blocker. In rare cases, propylthiouracil treatment may be required. Gestational transient thyrotoxicosis is not associated with detrimental outcomes.

Case continued

Our patient’s TSH level is low and her free T₄ and T₃ levels are elevated. Her high beta-hCG level may be stimulating the thyroid gland and may account for the low TSH value, as well as for her tachycardia, emesis, shortness of breath, and weight loss.

After an obstetric consult, it is determined that our patient has a viable pregnancy. However, further investigation with transvaginal ultrasonography reveals that she has two viable, single-placenta, intrauterine gestations, separated by a thin chorionic membrane.

Beta-hCG and free T₄ levels are significantly higher in twin pregnancies than in single pregnancies, especially in the early stages.⁶ In our patient, the twin pregnancy led to the elevated beta-hCG, which eventually manifested as thyrotoxicosis, which caused the shortness of breath, hyperemesis, weight loss, tachycardia, and nausea.

Shortness of breath in patients with thyrotoxicosis is well recognized but not well explained. It may be caused by decreased lung compliance, engorged capillaries in the lung, or left ventricular failure, as well as by chest pain due to increased myocardial demand or coronary artery vasospasm.⁴ The dyspnea is present at rest and during exertion, and the high metabolic rate is thought to lead to an inappropriate response of the ventilatory system.^3,8

WHAT TREATMENT?

4. How would you treat this patient at this point?

• No drug therapy, just supportive care
• Propranolol (Inderal)
• Levothyroxine
• Propylthiouracil

Several types of drugs are used to manage hyperthyroidism.

Antithyroid drugs such as propylthiouracil, methimazole (Northyx, Tapazole), and carbimazole block thyroid hormone synthesis by inhibiting thyroid peroxidase. Propylthiouracil also blocks peripheral conversion of T₄ to T₃. Side effects of these agents include abnormal sense of taste, pruritus, urticaria, agranulocytosis, and hepatotoxicity.⁴

Usually, hyperthyroidism is treated with propylthiouracil at the smallest effective dose. This has been proven to be safe to the fetus and mother during pregnancy.⁹ Propylthiouracil and the other drugs in its class cross the placenta, but propylthiouracil crosses at one-quarter the rate of the other two.⁹

Beta-blockers are effective in the acute phase of thyrotoxicosis against tachycardia, hypertension, and atrial fibrillation. They also decrease conversion of T₄ to T₃, which is an added benefit. Beta-blockers can be tapered as thyroid hormone levels decrease.

A short course of a short-acting beta-blocker would be an option for our patient and would decrease her symptoms, although she does not have the typical markedly elevated T₄ or T₃ levels. In the long term, a beta-blocker would present a fetal risk, but short courses can be tolerated without incident.⁹

Radioactive iodine 131 is used in patients with Graves disease. ¹³¹Iodine therapy is safe for most adults, but in pregnancy its use is contraindicated. Fetal thyroid tissue is thought to be present after 10 weeks of gestation and could be damaged by the use of radioactive iodine. Another warning with the use of radioactive iodine is that patients should avoid close contact with other adults for a few days after treatment, and should avoid close contact with children and pregnant women for 2 to 3 weeks after treatment because of the risk of exposure to radiation emanating from the thyroid gland.

Levothyroxine is a treatment for hypothyroidism, not hyperthyroidism.

CASE CONTINUED

Our patient is treated with propranolol and monitored for several days in the hospital, during which her symptoms markedly improve. She is discharged without complications.

TAKE-HOME POINTS

The evaluation of shortness of breath in adult patients can be difficult, given the many possible causes. It is especially challenging in pregnant patients, since normal physiologic changes of pregnancy may produce these symptoms.

In many instances, cardiomyopathy must be suspected if a pregnant patient complains of shortness of breath. However, it is not the only possible cause.

You responded to the parts of Dr. Lansdale’s commentary that struck a personal chord. Almost all responders shared his frustration. Many wrote that the American payer system fails to appropriately reward internists and primary care providers and called for restructuring the Medicare and third-party payer systems. Some of you took umbrage at his contention that hospitals are not safe, and that health care delivery systems do not always place quality care above economic imperatives as new programs and “centers of excellence” are implemented. And some of you reacted to the issues of physician satisfaction and difficulties in providing quality care in hospitals regulated by multiple agencies that generate unfunded mandates, while the hospitals already require high numbers of patients in order to survive financially.

I recently did a stint as rheumatology consultant at my hospital, and Dr. Lansdale’s commentary was fresh in my mind. I noticed with satisfaction that the physicians and nurses were using foam antiseptic on their hands. I noted the new checks on verbal orders and a successful emphasis on preventing deep vein thrombosis and bedsores. But I also noted more patient hand-offs between house staff and faculty, and difficulty in finding doctors who actually knew the patient (or doctors that patients recognized as being responsible for their care).

The electronic medical record is legible and available from all over the hospital, and I could tell who signed the notes. But many notes were actually cut-and-pasted from earlier notes, and thus I couldn’t always be sure who actually had said what and when. Technology is not an immediate panacea for the problem of limited physician time!

The house staff “lab” in the hospital with its microscope was closed due to regulatory concerns; thus, there was no easy way to look at a freshly spun urine sample for evidence of glomerulonephritis. This turned out to be a detriment to effective patient care: urine samples sent to the regular laboratory (with the usual transportation delay) rarely if ever reveal cellular casts. But we found creative, if inefficient, ways to deal with this and other problems.

At the end of the day, I realized that I still enjoy my time in the hospital. Patients’ problems can be presented to house staff and students at the bedside and their diagnoses and therapies discussed in real time. Junior physicians can observe how senior physicians talk to patients and families, including the many ways we have learned to say “I don’t know,” and learn to appreciate the value of a well-directed physical examination. There is still a synergy and intellectual satisfaction in being one of a group of senior consultants discussing the care of a shared patient who has complex medical problems.

With rational and caring involvement, individual physicians can alter the trajectory of patient management and remain the primary patient advocates within a health care system that can’t always easily deliver the quality that everyone desires. Caring, patient-focused physicians must remain in charge of health care delivery, lest we pay attention only to the financial and regulatory problems.

Tom, I am older and even more cynical than I was when we roamed the hospital together every third night and never went home on our post-call day until the last laboratory result had been checked and the last transfusion had been given. We inefficiently examined every patient’s urine ourselves (even from those being admitted for cardiac catheterization), and we had to convince patients of the (apparent) need for the urgent 3 AM blood draw to evaluate their 100.5° fever before we prepped the area and drew the blood. We drew blood for sedimentation rates and checked rapid plasma reagins at every admission and checked for urinary light chains in everyone with an elevated creatinine level and anemia, “just to be sure.” We blindly placed Swan-Ganz catheters to monitor many hypotensive patients in the intensive care units, and we aspirated pleural effusions on the basis of our percussive examination. We talked to patients and accepted enormous individual responsibility for their care, but we were also frequently numbed by the overwhelming intensity of the training and the practice.

I am all too aware of the many forces that are eroding physician-patient relationships and that can corrupt patient care in the name of efficiency, financial necessity, marketing advantage, or regulatory compliance. Many of these forces I hope to help change. But I remain a hospital guy because I can still make a difference. I still feel honored that patients entrust their care to me as we attempt to navigate our evolving and, yes, sometimes treacherous medical system. Evading the crocodiles and fighting insurance companies are now in my job description.

In this issue we run two letters in response to Dr. Lansdale’s commentary. In December we will publish more letters, though due to space limitations some will be abridged. We plan to run full text of many of the letters online at www.ccjm.org in December.

You responded to the parts of Dr. Lansdale’s commentary that struck a personal chord. Almost all responders shared his frustration. Many wrote that the American payer system fails to appropriately reward internists and primary care providers and called for restructuring the Medicare and third-party payer systems. Some of you took umbrage at his contention that hospitals are not safe, and that health care delivery systems do not always place quality care above economic imperatives as new programs and “centers of excellence” are implemented. And some of you reacted to the issues of physician satisfaction and difficulties in providing quality care in hospitals regulated by multiple agencies that generate unfunded mandates, while the hospitals already require high numbers of patients in order to survive financially.

I recently did a stint as rheumatology consultant at my hospital, and Dr. Lansdale’s commentary was fresh in my mind. I noticed with satisfaction that the physicians and nurses were using foam antiseptic on their hands. I noted the new checks on verbal orders and a successful emphasis on preventing deep vein thrombosis and bedsores. But I also noted more patient hand-offs between house staff and faculty, and difficulty in finding doctors who actually knew the patient (or doctors that patients recognized as being responsible for their care).

The electronic medical record is legible and available from all over the hospital, and I could tell who signed the notes. But many notes were actually cut-and-pasted from earlier notes, and thus I couldn’t always be sure who actually had said what and when. Technology is not an immediate panacea for the problem of limited physician time!

The house staff “lab” in the hospital with its microscope was closed due to regulatory concerns; thus, there was no easy way to look at a freshly spun urine sample for evidence of glomerulonephritis. This turned out to be a detriment to effective patient care: urine samples sent to the regular laboratory (with the usual transportation delay) rarely if ever reveal cellular casts. But we found creative, if inefficient, ways to deal with this and other problems.

At the end of the day, I realized that I still enjoy my time in the hospital. Patients’ problems can be presented to house staff and students at the bedside and their diagnoses and therapies discussed in real time. Junior physicians can observe how senior physicians talk to patients and families, including the many ways we have learned to say “I don’t know,” and learn to appreciate the value of a well-directed physical examination. There is still a synergy and intellectual satisfaction in being one of a group of senior consultants discussing the care of a shared patient who has complex medical problems.

With rational and caring involvement, individual physicians can alter the trajectory of patient management and remain the primary patient advocates within a health care system that can’t always easily deliver the quality that everyone desires. Caring, patient-focused physicians must remain in charge of health care delivery, lest we pay attention only to the financial and regulatory problems.

Tom, I am older and even more cynical than I was when we roamed the hospital together every third night and never went home on our post-call day until the last laboratory result had been checked and the last transfusion had been given. We inefficiently examined every patient’s urine ourselves (even from those being admitted for cardiac catheterization), and we had to convince patients of the (apparent) need for the urgent 3 AM blood draw to evaluate their 100.5° fever before we prepped the area and drew the blood. We drew blood for sedimentation rates and checked rapid plasma reagins at every admission and checked for urinary light chains in everyone with an elevated creatinine level and anemia, “just to be sure.” We blindly placed Swan-Ganz catheters to monitor many hypotensive patients in the intensive care units, and we aspirated pleural effusions on the basis of our percussive examination. We talked to patients and accepted enormous individual responsibility for their care, but we were also frequently numbed by the overwhelming intensity of the training and the practice.

I am all too aware of the many forces that are eroding physician-patient relationships and that can corrupt patient care in the name of efficiency, financial necessity, marketing advantage, or regulatory compliance. Many of these forces I hope to help change. But I remain a hospital guy because I can still make a difference. I still feel honored that patients entrust their care to me as we attempt to navigate our evolving and, yes, sometimes treacherous medical system. Evading the crocodiles and fighting insurance companies are now in my job description.

In this issue we run two letters in response to Dr. Lansdale’s commentary. In December we will publish more letters, though due to space limitations some will be abridged. We plan to run full text of many of the letters online at www.ccjm.org in December.

You responded to the parts of Dr. Lansdale’s commentary that struck a personal chord. Almost all responders shared his frustration. Many wrote that the American payer system fails to appropriately reward internists and primary care providers and called for restructuring the Medicare and third-party payer systems. Some of you took umbrage at his contention that hospitals are not safe, and that health care delivery systems do not always place quality care above economic imperatives as new programs and “centers of excellence” are implemented. And some of you reacted to the issues of physician satisfaction and difficulties in providing quality care in hospitals regulated by multiple agencies that generate unfunded mandates, while the hospitals already require high numbers of patients in order to survive financially.

I recently did a stint as rheumatology consultant at my hospital, and Dr. Lansdale’s commentary was fresh in my mind. I noticed with satisfaction that the physicians and nurses were using foam antiseptic on their hands. I noted the new checks on verbal orders and a successful emphasis on preventing deep vein thrombosis and bedsores. But I also noted more patient hand-offs between house staff and faculty, and difficulty in finding doctors who actually knew the patient (or doctors that patients recognized as being responsible for their care).

The electronic medical record is legible and available from all over the hospital, and I could tell who signed the notes. But many notes were actually cut-and-pasted from earlier notes, and thus I couldn’t always be sure who actually had said what and when. Technology is not an immediate panacea for the problem of limited physician time!

The house staff “lab” in the hospital with its microscope was closed due to regulatory concerns; thus, there was no easy way to look at a freshly spun urine sample for evidence of glomerulonephritis. This turned out to be a detriment to effective patient care: urine samples sent to the regular laboratory (with the usual transportation delay) rarely if ever reveal cellular casts. But we found creative, if inefficient, ways to deal with this and other problems.

At the end of the day, I realized that I still enjoy my time in the hospital. Patients’ problems can be presented to house staff and students at the bedside and their diagnoses and therapies discussed in real time. Junior physicians can observe how senior physicians talk to patients and families, including the many ways we have learned to say “I don’t know,” and learn to appreciate the value of a well-directed physical examination. There is still a synergy and intellectual satisfaction in being one of a group of senior consultants discussing the care of a shared patient who has complex medical problems.

With rational and caring involvement, individual physicians can alter the trajectory of patient management and remain the primary patient advocates within a health care system that can’t always easily deliver the quality that everyone desires. Caring, patient-focused physicians must remain in charge of health care delivery, lest we pay attention only to the financial and regulatory problems.

Tom, I am older and even more cynical than I was when we roamed the hospital together every third night and never went home on our post-call day until the last laboratory result had been checked and the last transfusion had been given. We inefficiently examined every patient’s urine ourselves (even from those being admitted for cardiac catheterization), and we had to convince patients of the (apparent) need for the urgent 3 AM blood draw to evaluate their 100.5° fever before we prepped the area and drew the blood. We drew blood for sedimentation rates and checked rapid plasma reagins at every admission and checked for urinary light chains in everyone with an elevated creatinine level and anemia, “just to be sure.” We blindly placed Swan-Ganz catheters to monitor many hypotensive patients in the intensive care units, and we aspirated pleural effusions on the basis of our percussive examination. We talked to patients and accepted enormous individual responsibility for their care, but we were also frequently numbed by the overwhelming intensity of the training and the practice.

I am all too aware of the many forces that are eroding physician-patient relationships and that can corrupt patient care in the name of efficiency, financial necessity, marketing advantage, or regulatory compliance. Many of these forces I hope to help change. But I remain a hospital guy because I can still make a difference. I still feel honored that patients entrust their care to me as we attempt to navigate our evolving and, yes, sometimes treacherous medical system. Evading the crocodiles and fighting insurance companies are now in my job description.

In this issue we run two letters in response to Dr. Lansdale’s commentary. In December we will publish more letters, though due to space limitations some will be abridged. We plan to run full text of many of the letters online at www.ccjm.org in December.

Did PSA finding get lost in the shuffle?

A SCREENING PROSTATE-SPECIFIC ANTIGEN (PSA) TEST ordered for a 76-year-old man by his primary care physician was within normal limits at 3.1. Two years later, the patient saw a urologist, who diagnosed renal cysts and bladder trabeculation based on a CT scan. Five months after that, the primary care physician ordered a second screening PSA, which was elevated at 12.

About a week later, the primary care physician noted that the patient was scheduled to see the urologist the next day, but didn’t indicate that the urologist had been informed of the elevated PSA or that the patient had been told of its significance. A letter from the primary care physician to the urologist after the patient’s visit stated that the patient was being treated for microscopic hematuria but didn’t mention elevated PSA. A letter several weeks later from the urologist to the primary care physician discussed the patient’s elevated PSA. The primary care physician didn’t contact the urologist to follow up on the finding, however.

After a year of testing, the urologist concluded that the hematuria was probably related to the kidney, or perhaps the prostate, and started the patient on dutasteride, which helped the bleeding. Two months after the start of treatment, the urologist ordered a PSA test, which was extremely elevated. A subsequent biopsy revealed adenocarcinoma, and a bone scan showed metastatic bony disease, which hadn’t shown up on a bone scan done 6 months before. The patient died 2 years later. The cause of death was listed as cardiopulmonary arrest, cardiogenic shock, and myocardial infarction.

PLAINTIFF’S CLAIM The plaintiff’s claim focused on the handling of the PSA test, though the specifics of the claim were not detailed in the case summary.

DOCTOR’S DEFENSE The primary care physician claimed that his nurse told the patient after the second PSA test that the PSA was 12 and encouraged the patient to see the urologist to discuss the elevated level. The physician also claimed that he had faxed the elevated PSA test result to the urologist and that the patient was reminded of the elevated PSA during his visit to the urologist. No information about the urologist’s defense was available.

VERDICT $325,000 Massachusetts settlement.

COMMENT Coordination of care and documentation of communication are keys to good patient care—and avoiding lawsuits.

Woman sent home from ER dies of aneurysm

SEVERE HEADACHES prompted a 38-year-old woman to visit her family physician, who referred her to a neurologist; an appointment was scheduled for more than a month later. A month after seeing the family physician, the patient went to the emergency room complaining of a severe headache.

A CT scan ordered by the ER physician showed a large mass in the patient’s brain. The ER physician gave the patient the scan report, told her to see her family doctor, and sent her home without consulting a neurosurgeon. Later that day, the aneurysm ruptured; the patient’s family took her to the hospital, where she died the next morning.

PLAINTIFF’S CLAIM The family physician should have ordered a CT scan, which would have revealed the aneurysm. The ER physician should have ordered an immediate neurologic consult, which would have led to surgical repair of the leaking aneurysm. Either measure would have saved the patient’s life.

DOCTOR’S DEFENSE The family physician claimed that the patient’s complaints weren’t urgent and he made a proper referral. The ER physician claimed that the patient wouldn’t have lived even if he’d arranged an immediate consult.

VERDICT $1.5 million Michigan verdict against the ER physician.

COMMENT This case illustrates the value of clearly documenting referrals and suggesting follow-up if a change in symptoms occurs.

Jaundiced newborn dies after slip-ups

AN INFANT BORN AT 36 WEEKS and the baby’s 20-year-old mother were discharged from the hospital fewer than 48 hours after delivery, with an appointment with a visiting nurse for the following day and a pediatrician 3 days later. Hospital medical records reported infrequent breast feeding, significant decrease in weight, and a bruise on the back of the infant’s head.

The visiting nurse who examined the baby noted moderate facial jaundice, mild jaundice in the groin, and slight jaundice in the sclera of the eyes, as well as the bruise on the back of the head. The nurse didn’t notify the pediatrician of the jaundice. The mother said that when she voiced concern about the jaundice, the nurse told her to feed the infant more often and expose her to sunlight.

The day after the nurse’s visit, the parents noticed that the baby was more jaundiced and had started to arch her back, grunt, and whine. The mother called the pediatrician’s office that day and reported the symptoms; the nurse told her that the pediatrician felt that he didn’t need to see the baby before her appointment the following day. As the symptoms worsened, the mother called the pediatrician’s office 3 more times before 6 PM, speaking with 2 nurses, neither of whom took a medical history.

The mother called again after the office had closed. A nurse arranged for the infant to be seen at the hospital, where the baby was admitted with a critically low temperature, decreased muscle tone, arching of the back, and an elevated bilirubin level of 35.4 mg/dL. Despite phototherapy and intubation, the infant’s condition deteriorated, and she was airlifted to another medical facility for more advanced care. The baby was given cardiopulmonary resuscitation on arrival, but died 4 hours later of acute bilirubin encephalopathy.

PLAINTIFF’S CLAIM In light of her symptoms, the baby shouldn’t have been discharged from the hospital. The visiting nurse should have reported the baby’s symptoms to the pediatrician or recommended that the parents take the baby to the doctor right away. The nurses in the pediatrician’s office were negligent in not taking a full medical history. The pediatrician should have seen the baby immediately. He failed to recognize the symptoms of possible hyperbilirubinemia, a medical emergency.

DOCTOR’S DEFENSE No information about the doctor’s or nurses’ defense is available.

VERDICT $460,000 Massachusetts settlement.

COMMENT This case illustrates, once again, the importance of care coordination and sharing information on a timely basis.

Did PSA finding get lost in the shuffle?

A SCREENING PROSTATE-SPECIFIC ANTIGEN (PSA) TEST ordered for a 76-year-old man by his primary care physician was within normal limits at 3.1. Two years later, the patient saw a urologist, who diagnosed renal cysts and bladder trabeculation based on a CT scan. Five months after that, the primary care physician ordered a second screening PSA, which was elevated at 12.

About a week later, the primary care physician noted that the patient was scheduled to see the urologist the next day, but didn’t indicate that the urologist had been informed of the elevated PSA or that the patient had been told of its significance. A letter from the primary care physician to the urologist after the patient’s visit stated that the patient was being treated for microscopic hematuria but didn’t mention elevated PSA. A letter several weeks later from the urologist to the primary care physician discussed the patient’s elevated PSA. The primary care physician didn’t contact the urologist to follow up on the finding, however.

After a year of testing, the urologist concluded that the hematuria was probably related to the kidney, or perhaps the prostate, and started the patient on dutasteride, which helped the bleeding. Two months after the start of treatment, the urologist ordered a PSA test, which was extremely elevated. A subsequent biopsy revealed adenocarcinoma, and a bone scan showed metastatic bony disease, which hadn’t shown up on a bone scan done 6 months before. The patient died 2 years later. The cause of death was listed as cardiopulmonary arrest, cardiogenic shock, and myocardial infarction.

PLAINTIFF’S CLAIM The plaintiff’s claim focused on the handling of the PSA test, though the specifics of the claim were not detailed in the case summary.

DOCTOR’S DEFENSE The primary care physician claimed that his nurse told the patient after the second PSA test that the PSA was 12 and encouraged the patient to see the urologist to discuss the elevated level. The physician also claimed that he had faxed the elevated PSA test result to the urologist and that the patient was reminded of the elevated PSA during his visit to the urologist. No information about the urologist’s defense was available.

VERDICT $325,000 Massachusetts settlement.

COMMENT Coordination of care and documentation of communication are keys to good patient care—and avoiding lawsuits.

Woman sent home from ER dies of aneurysm

SEVERE HEADACHES prompted a 38-year-old woman to visit her family physician, who referred her to a neurologist; an appointment was scheduled for more than a month later. A month after seeing the family physician, the patient went to the emergency room complaining of a severe headache.

A CT scan ordered by the ER physician showed a large mass in the patient’s brain. The ER physician gave the patient the scan report, told her to see her family doctor, and sent her home without consulting a neurosurgeon. Later that day, the aneurysm ruptured; the patient’s family took her to the hospital, where she died the next morning.

PLAINTIFF’S CLAIM The family physician should have ordered a CT scan, which would have revealed the aneurysm. The ER physician should have ordered an immediate neurologic consult, which would have led to surgical repair of the leaking aneurysm. Either measure would have saved the patient’s life.

DOCTOR’S DEFENSE The family physician claimed that the patient’s complaints weren’t urgent and he made a proper referral. The ER physician claimed that the patient wouldn’t have lived even if he’d arranged an immediate consult.

VERDICT $1.5 million Michigan verdict against the ER physician.

COMMENT This case illustrates the value of clearly documenting referrals and suggesting follow-up if a change in symptoms occurs.

Jaundiced newborn dies after slip-ups

AN INFANT BORN AT 36 WEEKS and the baby’s 20-year-old mother were discharged from the hospital fewer than 48 hours after delivery, with an appointment with a visiting nurse for the following day and a pediatrician 3 days later. Hospital medical records reported infrequent breast feeding, significant decrease in weight, and a bruise on the back of the infant’s head.

The visiting nurse who examined the baby noted moderate facial jaundice, mild jaundice in the groin, and slight jaundice in the sclera of the eyes, as well as the bruise on the back of the head. The nurse didn’t notify the pediatrician of the jaundice. The mother said that when she voiced concern about the jaundice, the nurse told her to feed the infant more often and expose her to sunlight.

The day after the nurse’s visit, the parents noticed that the baby was more jaundiced and had started to arch her back, grunt, and whine. The mother called the pediatrician’s office that day and reported the symptoms; the nurse told her that the pediatrician felt that he didn’t need to see the baby before her appointment the following day. As the symptoms worsened, the mother called the pediatrician’s office 3 more times before 6 PM, speaking with 2 nurses, neither of whom took a medical history.

The mother called again after the office had closed. A nurse arranged for the infant to be seen at the hospital, where the baby was admitted with a critically low temperature, decreased muscle tone, arching of the back, and an elevated bilirubin level of 35.4 mg/dL. Despite phototherapy and intubation, the infant’s condition deteriorated, and she was airlifted to another medical facility for more advanced care. The baby was given cardiopulmonary resuscitation on arrival, but died 4 hours later of acute bilirubin encephalopathy.

PLAINTIFF’S CLAIM In light of her symptoms, the baby shouldn’t have been discharged from the hospital. The visiting nurse should have reported the baby’s symptoms to the pediatrician or recommended that the parents take the baby to the doctor right away. The nurses in the pediatrician’s office were negligent in not taking a full medical history. The pediatrician should have seen the baby immediately. He failed to recognize the symptoms of possible hyperbilirubinemia, a medical emergency.

DOCTOR’S DEFENSE No information about the doctor’s or nurses’ defense is available.

VERDICT $460,000 Massachusetts settlement.

COMMENT This case illustrates, once again, the importance of care coordination and sharing information on a timely basis.

Did PSA finding get lost in the shuffle?

A SCREENING PROSTATE-SPECIFIC ANTIGEN (PSA) TEST ordered for a 76-year-old man by his primary care physician was within normal limits at 3.1. Two years later, the patient saw a urologist, who diagnosed renal cysts and bladder trabeculation based on a CT scan. Five months after that, the primary care physician ordered a second screening PSA, which was elevated at 12.

About a week later, the primary care physician noted that the patient was scheduled to see the urologist the next day, but didn’t indicate that the urologist had been informed of the elevated PSA or that the patient had been told of its significance. A letter from the primary care physician to the urologist after the patient’s visit stated that the patient was being treated for microscopic hematuria but didn’t mention elevated PSA. A letter several weeks later from the urologist to the primary care physician discussed the patient’s elevated PSA. The primary care physician didn’t contact the urologist to follow up on the finding, however.

After a year of testing, the urologist concluded that the hematuria was probably related to the kidney, or perhaps the prostate, and started the patient on dutasteride, which helped the bleeding. Two months after the start of treatment, the urologist ordered a PSA test, which was extremely elevated. A subsequent biopsy revealed adenocarcinoma, and a bone scan showed metastatic bony disease, which hadn’t shown up on a bone scan done 6 months before. The patient died 2 years later. The cause of death was listed as cardiopulmonary arrest, cardiogenic shock, and myocardial infarction.

PLAINTIFF’S CLAIM The plaintiff’s claim focused on the handling of the PSA test, though the specifics of the claim were not detailed in the case summary.

DOCTOR’S DEFENSE The primary care physician claimed that his nurse told the patient after the second PSA test that the PSA was 12 and encouraged the patient to see the urologist to discuss the elevated level. The physician also claimed that he had faxed the elevated PSA test result to the urologist and that the patient was reminded of the elevated PSA during his visit to the urologist. No information about the urologist’s defense was available.

VERDICT $325,000 Massachusetts settlement.

COMMENT Coordination of care and documentation of communication are keys to good patient care—and avoiding lawsuits.

Woman sent home from ER dies of aneurysm

SEVERE HEADACHES prompted a 38-year-old woman to visit her family physician, who referred her to a neurologist; an appointment was scheduled for more than a month later. A month after seeing the family physician, the patient went to the emergency room complaining of a severe headache.

A CT scan ordered by the ER physician showed a large mass in the patient’s brain. The ER physician gave the patient the scan report, told her to see her family doctor, and sent her home without consulting a neurosurgeon. Later that day, the aneurysm ruptured; the patient’s family took her to the hospital, where she died the next morning.

PLAINTIFF’S CLAIM The family physician should have ordered a CT scan, which would have revealed the aneurysm. The ER physician should have ordered an immediate neurologic consult, which would have led to surgical repair of the leaking aneurysm. Either measure would have saved the patient’s life.

DOCTOR’S DEFENSE The family physician claimed that the patient’s complaints weren’t urgent and he made a proper referral. The ER physician claimed that the patient wouldn’t have lived even if he’d arranged an immediate consult.

VERDICT $1.5 million Michigan verdict against the ER physician.

COMMENT This case illustrates the value of clearly documenting referrals and suggesting follow-up if a change in symptoms occurs.

Jaundiced newborn dies after slip-ups

AN INFANT BORN AT 36 WEEKS and the baby’s 20-year-old mother were discharged from the hospital fewer than 48 hours after delivery, with an appointment with a visiting nurse for the following day and a pediatrician 3 days later. Hospital medical records reported infrequent breast feeding, significant decrease in weight, and a bruise on the back of the infant’s head.

The visiting nurse who examined the baby noted moderate facial jaundice, mild jaundice in the groin, and slight jaundice in the sclera of the eyes, as well as the bruise on the back of the head. The nurse didn’t notify the pediatrician of the jaundice. The mother said that when she voiced concern about the jaundice, the nurse told her to feed the infant more often and expose her to sunlight.

The day after the nurse’s visit, the parents noticed that the baby was more jaundiced and had started to arch her back, grunt, and whine. The mother called the pediatrician’s office that day and reported the symptoms; the nurse told her that the pediatrician felt that he didn’t need to see the baby before her appointment the following day. As the symptoms worsened, the mother called the pediatrician’s office 3 more times before 6 PM, speaking with 2 nurses, neither of whom took a medical history.

The mother called again after the office had closed. A nurse arranged for the infant to be seen at the hospital, where the baby was admitted with a critically low temperature, decreased muscle tone, arching of the back, and an elevated bilirubin level of 35.4 mg/dL. Despite phototherapy and intubation, the infant’s condition deteriorated, and she was airlifted to another medical facility for more advanced care. The baby was given cardiopulmonary resuscitation on arrival, but died 4 hours later of acute bilirubin encephalopathy.

PLAINTIFF’S CLAIM In light of her symptoms, the baby shouldn’t have been discharged from the hospital. The visiting nurse should have reported the baby’s symptoms to the pediatrician or recommended that the parents take the baby to the doctor right away. The nurses in the pediatrician’s office were negligent in not taking a full medical history. The pediatrician should have seen the baby immediately. He failed to recognize the symptoms of possible hyperbilirubinemia, a medical emergency.

DOCTOR’S DEFENSE No information about the doctor’s or nurses’ defense is available.

VERDICT $460,000 Massachusetts settlement.

COMMENT This case illustrates, once again, the importance of care coordination and sharing information on a timely basis.

When patients reached a certain age (36 for men, 46 for women), it used to mean that it was time, in the eyes of the United States Preventive Services Task Force (USPSTF), to screen for lipid disorders. But that’s changed for female patients.

The USPSTF’s latest recommendations (TABLE 1) on screening for lipid disorders in adults¹ call for screening women only when coronary heart disease (CHD) risk factors are present, regardless of their age. (See TABLE 2 for a list of CHD risk factors.) That’s a major shift from the 2001 recommendation, which stated that all women over age 45 should be screened and women ages 20 to 45 should be screened if they were at elevated risk.

The recommendations for men remain the same: All men older than 35 should be screened, as should men who are between the ages of 20 and 35 who have other CHD risks.

TABLE 1
USPSTF lipid disorder screening recommendations at a glance

TABLE 2
Risk factors for CHD

A different approach from NIH and AHA

The revised updated recommendation for women over age 45 was based on 2 systematic evidence reviews^2,3 that concluded, while treatment clearly benefits women with other risk factors, benefit has not been proven for women who are otherwise CHD risk free.

The recommendation for women conflicts with those of the National Institutes of Health and the American Heart Association; both recommend screening all adults starting at age 20—regardless of risk.

Screening those without risk isn’t ruled out

It is important to note that the task force is not recommending against screening in women (or men between the ages of 20 and 35) who do not have other CHD risks. The task force makes a C recommendation with wording that states, “The USPSTF makes no recommendation for or against routine provision of [the service]. The USPSTF found at least fair evidence that [the service] can improve health outcomes but concludes that the balance of benefits and harms is too close to justify a general recommendation” (TABLE 3).

The task force chose not to use the new wording for a C recommendation, adopted in 2007, which reads, “The USPSTF recommends against routinely providing the service. There may be considerations that support providing the service in an individual patient. There is at least moderate certainty that the net benefit is small.”

It is also important to realize that a large proportion of women have another CHD risk and will not fall into the C category recommendation.

TABLE 3
USPSTF recommendation categories

No need to look at triglycerides initially

The task force recommends screening with a fasting or nonfasting serum sample for total cholesterol and high-density lipoprotein cholesterol. The task force does not recommend including a triglyceride level because there is mixed and inclusive evidence that triglyceride levels are independently associated with CHD risk and scant evidence that treating isolated elevated triglyceride levels reduces the occurrence of CHD events. This approach also conflicts with other organizations that recommend screening with fasting lipid profiles that include a triglyceride level.

The task force states that an abnormal initial screen should be confirmed by a repeat test and, if confirmed, a fasting lipid panel should be obtained. Wide adoption of the task force recommendations would result in considerable savings in cost and patient inconvenience by avoiding complete fasting lipid panels as the initial screen.

The optimal frequency of screening is not established and the task force states that every 5 years is reasonable, although more frequent testing might be considered for those with high normal values, and less frequent intervals for those with optimal cholesterol levels and healthy lifestyles.

Treatment: Look beyond lifestyle

The screening recommendations are accompanied by a discussion of clinical considerations and a description of an approach to treatment for those with lipid disorders. The main point the task force makes is that all CHD risks should be addressed, and that lifestyle changes alone rarely reduce elevated cholesterol to an optimal level. (For more on the treatment of hyperlipidemia, see the National Heart, Lung, and Blood Institute’s Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults [Adult Treatment Panel III] at http://www.nhlbi.nih.gov/guidelines/cholesterol/index.htm.)

Time to rethink conventional opinion

The updated task force recommendations are a reminder that many widely used guidelines, including those on the prevention of CHD, are based on a lack of high-level evidence. Thus, it is not surprising that a rigorously evidence-based analysis, as preformed by the USPSTF, will frequently result in recommendations that are at variance with common practice and conventional opinion.

When patients reached a certain age (36 for men, 46 for women), it used to mean that it was time, in the eyes of the United States Preventive Services Task Force (USPSTF), to screen for lipid disorders. But that’s changed for female patients.

The USPSTF’s latest recommendations (TABLE 1) on screening for lipid disorders in adults¹ call for screening women only when coronary heart disease (CHD) risk factors are present, regardless of their age. (See TABLE 2 for a list of CHD risk factors.) That’s a major shift from the 2001 recommendation, which stated that all women over age 45 should be screened and women ages 20 to 45 should be screened if they were at elevated risk.

The recommendations for men remain the same: All men older than 35 should be screened, as should men who are between the ages of 20 and 35 who have other CHD risks.

TABLE 1
USPSTF lipid disorder screening recommendations at a glance

TABLE 2
Risk factors for CHD

A different approach from NIH and AHA

The revised updated recommendation for women over age 45 was based on 2 systematic evidence reviews^2,3 that concluded, while treatment clearly benefits women with other risk factors, benefit has not been proven for women who are otherwise CHD risk free.

The recommendation for women conflicts with those of the National Institutes of Health and the American Heart Association; both recommend screening all adults starting at age 20—regardless of risk.

Screening those without risk isn’t ruled out

It is important to note that the task force is not recommending against screening in women (or men between the ages of 20 and 35) who do not have other CHD risks. The task force makes a C recommendation with wording that states, “The USPSTF makes no recommendation for or against routine provision of [the service]. The USPSTF found at least fair evidence that [the service] can improve health outcomes but concludes that the balance of benefits and harms is too close to justify a general recommendation” (TABLE 3).

The task force chose not to use the new wording for a C recommendation, adopted in 2007, which reads, “The USPSTF recommends against routinely providing the service. There may be considerations that support providing the service in an individual patient. There is at least moderate certainty that the net benefit is small.”

It is also important to realize that a large proportion of women have another CHD risk and will not fall into the C category recommendation.

TABLE 3
USPSTF recommendation categories

No need to look at triglycerides initially

The task force recommends screening with a fasting or nonfasting serum sample for total cholesterol and high-density lipoprotein cholesterol. The task force does not recommend including a triglyceride level because there is mixed and inclusive evidence that triglyceride levels are independently associated with CHD risk and scant evidence that treating isolated elevated triglyceride levels reduces the occurrence of CHD events. This approach also conflicts with other organizations that recommend screening with fasting lipid profiles that include a triglyceride level.

The task force states that an abnormal initial screen should be confirmed by a repeat test and, if confirmed, a fasting lipid panel should be obtained. Wide adoption of the task force recommendations would result in considerable savings in cost and patient inconvenience by avoiding complete fasting lipid panels as the initial screen.

The optimal frequency of screening is not established and the task force states that every 5 years is reasonable, although more frequent testing might be considered for those with high normal values, and less frequent intervals for those with optimal cholesterol levels and healthy lifestyles.

Treatment: Look beyond lifestyle

The screening recommendations are accompanied by a discussion of clinical considerations and a description of an approach to treatment for those with lipid disorders. The main point the task force makes is that all CHD risks should be addressed, and that lifestyle changes alone rarely reduce elevated cholesterol to an optimal level. (For more on the treatment of hyperlipidemia, see the National Heart, Lung, and Blood Institute’s Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults [Adult Treatment Panel III] at http://www.nhlbi.nih.gov/guidelines/cholesterol/index.htm.)

Time to rethink conventional opinion

The updated task force recommendations are a reminder that many widely used guidelines, including those on the prevention of CHD, are based on a lack of high-level evidence. Thus, it is not surprising that a rigorously evidence-based analysis, as preformed by the USPSTF, will frequently result in recommendations that are at variance with common practice and conventional opinion.

When patients reached a certain age (36 for men, 46 for women), it used to mean that it was time, in the eyes of the United States Preventive Services Task Force (USPSTF), to screen for lipid disorders. But that’s changed for female patients.

The USPSTF’s latest recommendations (TABLE 1) on screening for lipid disorders in adults¹ call for screening women only when coronary heart disease (CHD) risk factors are present, regardless of their age. (See TABLE 2 for a list of CHD risk factors.) That’s a major shift from the 2001 recommendation, which stated that all women over age 45 should be screened and women ages 20 to 45 should be screened if they were at elevated risk.

The recommendations for men remain the same: All men older than 35 should be screened, as should men who are between the ages of 20 and 35 who have other CHD risks.

TABLE 1
USPSTF lipid disorder screening recommendations at a glance

TABLE 2
Risk factors for CHD

A different approach from NIH and AHA

The revised updated recommendation for women over age 45 was based on 2 systematic evidence reviews^2,3 that concluded, while treatment clearly benefits women with other risk factors, benefit has not been proven for women who are otherwise CHD risk free.

The recommendation for women conflicts with those of the National Institutes of Health and the American Heart Association; both recommend screening all adults starting at age 20—regardless of risk.

Screening those without risk isn’t ruled out

It is important to note that the task force is not recommending against screening in women (or men between the ages of 20 and 35) who do not have other CHD risks. The task force makes a C recommendation with wording that states, “The USPSTF makes no recommendation for or against routine provision of [the service]. The USPSTF found at least fair evidence that [the service] can improve health outcomes but concludes that the balance of benefits and harms is too close to justify a general recommendation” (TABLE 3).

The task force chose not to use the new wording for a C recommendation, adopted in 2007, which reads, “The USPSTF recommends against routinely providing the service. There may be considerations that support providing the service in an individual patient. There is at least moderate certainty that the net benefit is small.”

It is also important to realize that a large proportion of women have another CHD risk and will not fall into the C category recommendation.

TABLE 3
USPSTF recommendation categories

No need to look at triglycerides initially

The task force recommends screening with a fasting or nonfasting serum sample for total cholesterol and high-density lipoprotein cholesterol. The task force does not recommend including a triglyceride level because there is mixed and inclusive evidence that triglyceride levels are independently associated with CHD risk and scant evidence that treating isolated elevated triglyceride levels reduces the occurrence of CHD events. This approach also conflicts with other organizations that recommend screening with fasting lipid profiles that include a triglyceride level.

The task force states that an abnormal initial screen should be confirmed by a repeat test and, if confirmed, a fasting lipid panel should be obtained. Wide adoption of the task force recommendations would result in considerable savings in cost and patient inconvenience by avoiding complete fasting lipid panels as the initial screen.

The optimal frequency of screening is not established and the task force states that every 5 years is reasonable, although more frequent testing might be considered for those with high normal values, and less frequent intervals for those with optimal cholesterol levels and healthy lifestyles.

Treatment: Look beyond lifestyle

The screening recommendations are accompanied by a discussion of clinical considerations and a description of an approach to treatment for those with lipid disorders. The main point the task force makes is that all CHD risks should be addressed, and that lifestyle changes alone rarely reduce elevated cholesterol to an optimal level. (For more on the treatment of hyperlipidemia, see the National Heart, Lung, and Blood Institute’s Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults [Adult Treatment Panel III] at http://www.nhlbi.nih.gov/guidelines/cholesterol/index.htm.)

Time to rethink conventional opinion

The updated task force recommendations are a reminder that many widely used guidelines, including those on the prevention of CHD, are based on a lack of high-level evidence. Thus, it is not surprising that a rigorously evidence-based analysis, as preformed by the USPSTF, will frequently result in recommendations that are at variance with common practice and conventional opinion.

The University of Medicine and Dentistry of New Jersey (UMDNJ) owns a patent relating to the use of anti-Müllerian hormone/Müllerian inhibiting substance for predicting ovarian response in women with infertility. The patent is based in part on work that Dr. Seifer carried out while employed at UMDNJ. In accordance with UMDNJ policy, Dr. Seifer, a named inventor on this patent, assigned his interest in the invention to UMDNJ. UMDNJ has a licensing agreement with Diagnostic Systems Laboratory for the use of the claimed invention. Dr. Seifer receives a portion of the royalties, as determined by UMDNJ policy, that UMDNJ gains from this licensing agreement.

CASE: Borderline test result prompts referral

A 36-year-old nulliparous woman is seen in your office for evaluation after 6 months of infertility. She is ovulatory, and has been using an ovulation-prediction kit to time intercourse. You learn that she had Chlamydia trachomatis infection in the distant past, but elicit no other significant medical or surgical history. She reports that she smoked approximately one pack of cigarettes a day for 15 years but gave up smoking 5 years ago.

You order a hysterosalpingogram, followed by day 3 testing of follicle-stimulating hormone (FSH). The hysterosalpingogram is normal; the FSH level is 7.5 mIU/mL and the estradiol level is 30 pg/mL—both in the normal range.

The patient asks for testing of anti-Müllerian hormone (AMH; also known as Müllerian-inhibiting substance) because she has read that it is a new marker of fertility. The result is 0.5 ng/mL, a borderline value. After reviewing these results, you refer her to a reproductive endocrinologist for further management.

Was the test for AMH indicated? And is this referral appropriate?

The referral is entirely appropriate, even though the patient has not been trying to conceive for a full year. Why? The AMH value suggests that her ovarian reserve is in early decline. She would benefit from evaluation by a subspecialist who can review the entire spectrum of treatments, including aggressive options such as ovulation induction and in vitro fertilization (IVF), to optimize her reproductive success.

This article reviews the various biomarkers available to assess ovarian reserve in women who experience infertility:

• day 3 (basal) FSH
• clomiphene citrate challenge
• gonadotropin-releasing hormone (GnRH) agonist stimulation
• inhibin-B
• antral follicle count (AFC)
• AMH.

The AFC and AMH tend to detect the earliest changes in ovarian reserve, followed, sequentially, by inhibin-B, the clomiphene citrate challenge test (CCCT), and basal FSH.

The tests we describe are used primarily to assess treatment prognosis in infertile women. In time, however, appropriate population screening of ovarian reserve may be feasible to provide many more women with information about their reproductive potential and help them shape their life plan.

What makes a test valuable?

Ovarian reserve describes a woman’s reproductive potential—specifically, the number and quality of oocytes she possesses.¹ Biochemical tests of ovarian reserve emerged during the rise of assisted reproductive technologies (ART) in the late 1980s to predict both responsiveness to superovulation drugs and the odds of pregnancy with treatment.

Ideally, a test that assesses ovarian reserve should be affordable, straightforward, rapidly interpretable, and minimally invasive. It also should be able to detect changes that begin early in reproductive life. To be applicable to large populations of reproductive-age women, it should be of use anytime in the menstrual cycle, and should provide reproducible and highly accurate assessment of the reproductive aging process.

Our ability to offer tests that accurately measure ovarian reserve has a significant impact on women at risk of infertility and early menopause and on those who choose to delay childbearing for personal (nonmedical) reasons. These tests have become increasingly relevant because women are choosing to have their first child at a later age than their counterparts did 20 years ago:

• In 1980, 40% of women having their first baby were younger than 25 years, and only 5% were older than 35
• In 2000, 25% of women were younger than 25 when their first child was born, and 15% were older than 35.

Who should be tested?

Ovarian reserve is a complex clinical phenomenon that is influenced by age, genetics, and environmental variables. The decline in a woman’s ovarian reserve over time is irreversible; the trajectory of this decline is fundamental to the odds of fertility with age and the timing of the menopausal transition. At present, the markers used most often in clinical practice have some utility but also suffer from several drawbacks ( TABLE ).

For the general practitioner performing an infertility evaluation, we recommend focusing on the following groups of women for ovarian reserve testing:

• women over 30 years of age
• women with a history of exposure to a confirmed gonadotoxin, i.e., tobacco smoke, chemotherapy, radiation therapy
• women with a strong family history of early menopause or premature ovarian failure
• women who have had extensive ovarian surgery, i.e., cystectomy and unilateral oophorectomy.

Testing tends to have the highest yield in these groups. Women who have abnormal results should be referred to a reproductive endocrinologist for further evaluation and treatment.

The six tests are described below.

TABLE

How six markers of ovarian reserve stack up

1 | Basal FSH—widely used but only moderately informative

Day 3 FSH and the CCCT are the most widely used measures of ovarian reserve in ART practice. The use of early follicular-phase FSH as a marker of ovarian reserve and fertility was proposed 20 years ago with the emergence of IVF.^2-4 The test is an indirect assessment of ovarian reserve in that it measures pituitary production of FSH in response to feedback from ovarian hormones. Estradiol and inhibin-B reach a nadir early in the menstrual cycle; measuring FSH on day 3 offers a glimpse of the functioning of the hypothalamic–pituitary–ovarian axis before ovarian hormone levels rise later in the cycle ( FIGURE 1 ).^5,6

FIGURE 1 The HPO axis

The FSH level opens a window onto the function of the hypothalamic–pituitary–ovarian axis before ovarian hormone levels rise in the cycle. Women who have normal ovarian reserve have sufficient ovarian hormone production early in the menstrual cycle to maintain FSH levels within the normal range. Conversely, a “monotropic” elevation in FSH—one that is unaccompanied by a rise in luteinizing hormone (LH)—reflects poor hormone production from an aging pool of ovarian follicles and disinhibition of FSH production.^5,6

FSH measurements are typically combined with estradiol to enhance the sensitivity of testing ( FIGURE 2, ). Premature elevations of estradiol early in the follicular phase are driven by rising FSH levels in women with declining ovarian reserve. Abnormally elevated estrogen levels then feed back negatively on pituitary production of FSH and mask an elevation that might otherwise reveal diminished ovarian reserve. Measurement of both FSH and estradiol on cycle day 3 may therefore help decrease the incidence of false-negative testing.

Commonly cited criteria for normal ovarian reserve are:

• early follicular phase FSH, <10 mIU/mL
• estradiol, <80 pg/mL¹

It is extremely important to note, however, that these are general guidelines and that cutoffs are both laboratory- and practice-specific.

FIGURE 2 Monthly and lifetime variations in estradiol and FSH

How 17ß-estradiol and follicle-stimulating hormone levels vary over the menstrual cycle (top) and a woman’s lifetime (bottom).

2 | Clomiphene citrate—more sensitive than FSH testing

Like basal FSH testing, the CCCT is an indirect assessment of ovarian reserve. Unlike FSH testing, the CCCT is provocative. It involves administration of 100 mg of clomiphene citrate (Clomid) on days 5 through 9 of the menstrual cycle, with FSH and estradiol measured on days 3 and 10. Once clomiphene citrate is administered, FSH and LH levels rise, followed by an increase in estradiol and inhibin. Evidence suggests that the smaller follicular cohorts in women with diminished ovarian reserve produce less inhibin-B and estradiol and, therefore, less negative feedback on clomiphene-induced pituitary FSH release.^6,7 The result: persistent elevation of the day 10 FSH value and a positive screen for diminished ovarian reserve.

In some women, day 10 FSH is elevated even after a normal day 3 value. This makes the CCCT more sensitive than basal FSH testing; it can identify women who might go unrecognized if evaluated by day 3 FSH and estradiol levels alone.

More expensive and labor-intensive than the alternatives

Interpretation of the CCCT requires that FSH and estradiol both be assessed on days 3 and 10. An elevated FSH (≥10 mIU/mL) on either day indicates diminished ovarian reserve. As with basal FSH testing, elevated estradiol (≥80 pg/mL) on day 3 is considered abnormal. The day 10 estradiol value of the CCCT reflects whether or not clomiphene citrate was administered appropriately, and should be elevated. However, the significance of the day 10 estradiol level has been debated with respect to its predictive value for pregnancy in infertile populations.⁸

The addition of day 10 FSH assessment improves the sensitivity of the CCCT over basal FSH measurement, but makes it a more expensive and labor-intensive test ( TABLE ).^5,6 The CCCT involves administration of clomiphene citrate, a safe drug (though it can have side effects), and two blood draws instead of one. Nevertheless, both tests are relatively noninvasive, rapid measures of ovarian reserve.

Drawbacks of the tests

Both basal FSH testing and the CCCT are widely used, although support for their ability to predict ovarian reserve in the infertile population has been challenged recently. Newer data demonstrate that these tests are limited in their ability to predict outcome (pregnancy and response to superovulation drugs) in all but a narrow group of patients undergoing IVF. Performance is particularly limited in:

• young women
• women in the general infertility population who are not utilizing IVF.^9-13

Additional drawbacks of basal FSH testing and the CCCT include:

• significant variability of test results from cycle to cycle (intercycle variability)
• limited time frame within which the tests can be performed (intracycle variability).

The basal FSH test and CCCT have high specificity (98% to 99% for each) as an assessment of reproductive performance in infertile women and generate few false-positive results.^5,6 However, the high screen cutoffs that allow for such specificity come at a price: Few women will screen positive, and sensitivity of the tests is low (between 7% and 8% for basal FSH and between 25% and 40% for the CCCT). Such low sensitivity means that many women will not conceive after infertility treatment despite a normal test result.^5,11 Overall, the tests are not highly informative for many women who get tested.

Once abnormal, normal results are meaningless

Once an FSH level or the CCCT has ever been abnormal, the patient has diminished ovarian reserve; normal values in subsequent menstrual cycles do not improve the odds of pregnancy with treatment.¹⁴ This fact can be a significant source of confusion and frustration for patients.

3 | GnRH agonist stimulation —no better than FSH testing

This test was developed in the search for a very sensitive assessment of ovarian reserve. It was designed to uncover subtle abnormalities in pituitary and ovarian dynamics. It involves administering a gonadotropin-releasing hormone (GnRH) agonist such as leuprolide acetate (Lupron) on day 2 or 3 of the menstrual cycle and measuring pituitary and ovarian hormone responses.^5,15

One group of investigators demonstrated a correlation between stimulated estradiol levels and responsiveness during IVF,¹⁶ but other studies have shown that the test does not perform significantly better than day 3 FSH in predicting ovarian reserve.^17,18

The sensitivity of GnRH agonist testing for pregnancy is moderate (32% to 89%); specificity ranges from 79% to 97%.¹⁹

4 | Inhibin-B—not helpful when used alone

This glycoprotein hormone produced by granulosa cells of developing follicles is a direct measure of ovarian reserve when assessed in the early follicular phase of the menstrual cycle.²⁰ Women treated with IVF who have a low inhibin-B level—particularly when using cutoffs below the range of 45–80 pg/mL—have been shown to respond poorly to superovulation and have a lower pregnancy rate than women with high inhibin-B.^21,22 One group of investigators demonstrated that women with clinical evidence of diminished ovarian reserve but a normal FSH level also had low inhibin-B production, suggesting that it may be a more sensitive marker than FSH.²²

Inhibin-B testing involves a simple blood draw. However, the test has been incorporated into clinical assessment of ovarian reserve only to a limited degree, due to the lack of reliable assays and controversy concerning its prognostic value.²³

Because of these limitations, routine testing of serum inhibin-B in isolation of other markers of ovarian reserve is not recommended.

5 | Antral follicle count—good predictor of IVF outcome

Transvaginal ultrasonographic determination of the number of ovarian follicles that measure between 2 mm and 10 mm in diameter in the early follicular phase of the cycle yields the AFC. As a direct marker of the cohort of growing follicles in the early menstrual cycle, the AFC is believed to correlate strongly with the number of primordial follicles present in the ovary and, therefore, ovarian reserve. Total AFCs of less than 5 to 10 are suggestive of diminished ovarian reserve.^24,25

In IVF cycles, AFC has proven to be an accurate predictor of number of oocytes retrieved, risk of cycle cancellation, and odds of conception.^24,25 Some investigators have even suggested that, compared with other markers of ovarian reserve, AFC is the best independent predictor of outcome in IVF cycles.^7,26-27

In a group of normally cycling women with proven fertility, AFC also showed a strong correlation with age, declining slowly until age 37 and more rapidly thereafter.^28,29

AFC sensitivity for pregnancy is moderate and varies widely in published reports (8% to 60%), whereas specificity tends to be higher (33% to 96%).¹⁹

Drawbacks of AFC

• Because of the need to perform transvaginal ultrasonography, AFC is a more invasive and often more expensive test than hormonal biomarkers
• Accurate assessment of AFC requires an experienced sonographer and can be limited in patients who have had pelvic surgery or uterine fibroids and in those who are obese
• Moderate interobserver and intercycle variability of AFC determinations limits its reproducibility^29,30
• As with basal FSH measurement, the intercycle variability of AFC does not correlate well with IVF outcome in individual patients.³⁰

6 | Anti-Müllerian hormone— many advantages

The drawbacks of the tests just described— e.g., intercycle variability, lack of uniform cutoffs, and limited ability to predict IVF outcomes—make the development of more reliable measures of ovarian reserve a priority in reproductive medicine. AMH is a highly promising marker that appears to have many advantages over other tests and may have the greatest power to predict ovarian aging in women of reproductive age.

How it works

AMH is a glycoprotein growth factor and a member of the transforming growth factor-ß superfamily.³¹ It is primarily produced by the pool of early-growing follicles, which are believed to serve as a proxy for the number of primordial follicles in the ovary. The number of primordial follicles at a given point in time represents the ovarian reserve. AMH levels above 0.7 ng/mL are considered normal; values between 0.3 ng/mL and 0.7 ng/mL are consistent with borderline ovarian reserve, according to 2007 data from Reprosource Corp.

AMH has been studied as a marker of ovarian reserve for 6 years, with multiple reports describing declines in levels with age and with diminishing oocyte numbers. It is undetectable at menopause.³²

The age-related decline in AMH is gradual but measurable even in young women, consistently preceding changes in other markers of ovarian reserve such as FSH and inhibin-B.^32-35 The longitudinal changes in AMH have been demonstrated in ovulatory premenopausal women and healthy volunteers with proven fertility.^33,34 In one series of women followed over a mean of 4 years (ages 25 to 46), AMH testing was superior to day 3 FSH, inhibin-B, and AFC in its ability to predict the onset of cycle irregularity and the menopausal transition.³³

Does it predict oocyte quality?

AMH has performed well as a biomarker, comparable in most series to AFC and superior to FSH. AMH levels are strongly correlated with the number of oocytes retrieved during IVF and the odds of cycle cancellation due to poor response^35-41 —but does it accurately characterize oocyte quality, the other element of ovarian reserve?

Some reports have shown a strong association between AMH levels and surrogates of oocyte quality, including fertilization, oocyte morphology, embryo quality, and pregnancy and miscarriage rates,^36-41 but others have not.⁴² Some reports demonstrate a relationship between AMH and some but not all surrogate markers of oocyte quality.⁴⁰

Advantages of AMH

• It demonstrates minimal intracycle variability.^32,43-45 Compared with other markers of ovarian reserve, which must be measured early in the follicular phase of the menstrual cycle, AMH can be assessed at random times, making it a more convenient method for patients and physicians
• It demonstrates minimal intercycle variability^32,34
• AMH levels are not significantly affected by the hormonal changes of pregnancy, oral contraceptive use, or GnRH treatment, and can be measured in these settings.^46,47

Utility of AMH is limited in PCOS and obesity

The ability to use AMH as a marker of ovarian aging in women who have polycystic ovary syndrome (PCOS) and in women who are obese may be limited by the ovulatory dysfunction in these populations. Circulating levels of AMH are higher in women with PCOS than in unaffected women, a finding thought to be indicative of oligo-ovulation and poor follicular development in polycystic ovaries.^48-53

In a recent series investigating AMH levels in women with PCOS, AMH and the degree of insulin resistance were positively correlated, and the AMH level was negatively correlated with the number of menses in a year.⁴⁹ The consistently positive correlation between AMH and PCOS may suggest a future role for this marker as a diagnostic tool.

In obese women who do not have PCOS, AMH production may be lower than in women of normal weight. In a recent series, normally cycling obese women in the later reproductive years were shown to have an AMH level 70% lower than those in women who were not obese.⁵⁴ These differences have not been well studied in younger obese women.

Which test is best?

AMH may be preferable to the other tests to assess ovarian reserve because it can be measured any time during the menstrual cycle or between cycles. AMH measurement is also useful if a woman is taking oral contraceptives or leuprolide acetate because these medications may confound the results of the other test methods. In addition, AMH may be the earliest indicator of decline in ovarian reproductive function. As such, it may highlight cases that merit a search for other causes of infertility and make it possible to treat them in a timely manner.

Elevated AMH may reveal occult PCOS and warn of significant risk of ovarian hyperstimulation prior to ovulation induction with gonadotrophins, so that the clinician can plan smaller doses.

The University of Medicine and Dentistry of New Jersey (UMDNJ) owns a patent relating to the use of anti-Müllerian hormone/Müllerian inhibiting substance for predicting ovarian response in women with infertility. The patent is based in part on work that Dr. Seifer carried out while employed at UMDNJ. In accordance with UMDNJ policy, Dr. Seifer, a named inventor on this patent, assigned his interest in the invention to UMDNJ. UMDNJ has a licensing agreement with Diagnostic Systems Laboratory for the use of the claimed invention. Dr. Seifer receives a portion of the royalties, as determined by UMDNJ policy, that UMDNJ gains from this licensing agreement.

CASE: Borderline test result prompts referral

A 36-year-old nulliparous woman is seen in your office for evaluation after 6 months of infertility. She is ovulatory, and has been using an ovulation-prediction kit to time intercourse. You learn that she had Chlamydia trachomatis infection in the distant past, but elicit no other significant medical or surgical history. She reports that she smoked approximately one pack of cigarettes a day for 15 years but gave up smoking 5 years ago.

You order a hysterosalpingogram, followed by day 3 testing of follicle-stimulating hormone (FSH). The hysterosalpingogram is normal; the FSH level is 7.5 mIU/mL and the estradiol level is 30 pg/mL—both in the normal range.

The patient asks for testing of anti-Müllerian hormone (AMH; also known as Müllerian-inhibiting substance) because she has read that it is a new marker of fertility. The result is 0.5 ng/mL, a borderline value. After reviewing these results, you refer her to a reproductive endocrinologist for further management.

Was the test for AMH indicated? And is this referral appropriate?

The referral is entirely appropriate, even though the patient has not been trying to conceive for a full year. Why? The AMH value suggests that her ovarian reserve is in early decline. She would benefit from evaluation by a subspecialist who can review the entire spectrum of treatments, including aggressive options such as ovulation induction and in vitro fertilization (IVF), to optimize her reproductive success.

This article reviews the various biomarkers available to assess ovarian reserve in women who experience infertility:

• day 3 (basal) FSH
• clomiphene citrate challenge
• gonadotropin-releasing hormone (GnRH) agonist stimulation
• inhibin-B
• antral follicle count (AFC)
• AMH.

The AFC and AMH tend to detect the earliest changes in ovarian reserve, followed, sequentially, by inhibin-B, the clomiphene citrate challenge test (CCCT), and basal FSH.

The tests we describe are used primarily to assess treatment prognosis in infertile women. In time, however, appropriate population screening of ovarian reserve may be feasible to provide many more women with information about their reproductive potential and help them shape their life plan.

What makes a test valuable?

Ovarian reserve describes a woman’s reproductive potential—specifically, the number and quality of oocytes she possesses.¹ Biochemical tests of ovarian reserve emerged during the rise of assisted reproductive technologies (ART) in the late 1980s to predict both responsiveness to superovulation drugs and the odds of pregnancy with treatment.

Ideally, a test that assesses ovarian reserve should be affordable, straightforward, rapidly interpretable, and minimally invasive. It also should be able to detect changes that begin early in reproductive life. To be applicable to large populations of reproductive-age women, it should be of use anytime in the menstrual cycle, and should provide reproducible and highly accurate assessment of the reproductive aging process.

Our ability to offer tests that accurately measure ovarian reserve has a significant impact on women at risk of infertility and early menopause and on those who choose to delay childbearing for personal (nonmedical) reasons. These tests have become increasingly relevant because women are choosing to have their first child at a later age than their counterparts did 20 years ago:

• In 1980, 40% of women having their first baby were younger than 25 years, and only 5% were older than 35
• In 2000, 25% of women were younger than 25 when their first child was born, and 15% were older than 35.

Who should be tested?

Ovarian reserve is a complex clinical phenomenon that is influenced by age, genetics, and environmental variables. The decline in a woman’s ovarian reserve over time is irreversible; the trajectory of this decline is fundamental to the odds of fertility with age and the timing of the menopausal transition. At present, the markers used most often in clinical practice have some utility but also suffer from several drawbacks ( TABLE ).

For the general practitioner performing an infertility evaluation, we recommend focusing on the following groups of women for ovarian reserve testing:

• women over 30 years of age
• women with a history of exposure to a confirmed gonadotoxin, i.e., tobacco smoke, chemotherapy, radiation therapy
• women with a strong family history of early menopause or premature ovarian failure
• women who have had extensive ovarian surgery, i.e., cystectomy and unilateral oophorectomy.

Testing tends to have the highest yield in these groups. Women who have abnormal results should be referred to a reproductive endocrinologist for further evaluation and treatment.

The six tests are described below.

TABLE

How six markers of ovarian reserve stack up

1 | Basal FSH—widely used but only moderately informative

Day 3 FSH and the CCCT are the most widely used measures of ovarian reserve in ART practice. The use of early follicular-phase FSH as a marker of ovarian reserve and fertility was proposed 20 years ago with the emergence of IVF.^2-4 The test is an indirect assessment of ovarian reserve in that it measures pituitary production of FSH in response to feedback from ovarian hormones. Estradiol and inhibin-B reach a nadir early in the menstrual cycle; measuring FSH on day 3 offers a glimpse of the functioning of the hypothalamic–pituitary–ovarian axis before ovarian hormone levels rise later in the cycle ( FIGURE 1 ).^5,6

FIGURE 1 The HPO axis

The FSH level opens a window onto the function of the hypothalamic–pituitary–ovarian axis before ovarian hormone levels rise in the cycle. Women who have normal ovarian reserve have sufficient ovarian hormone production early in the menstrual cycle to maintain FSH levels within the normal range. Conversely, a “monotropic” elevation in FSH—one that is unaccompanied by a rise in luteinizing hormone (LH)—reflects poor hormone production from an aging pool of ovarian follicles and disinhibition of FSH production.^5,6

FSH measurements are typically combined with estradiol to enhance the sensitivity of testing ( FIGURE 2, ). Premature elevations of estradiol early in the follicular phase are driven by rising FSH levels in women with declining ovarian reserve. Abnormally elevated estrogen levels then feed back negatively on pituitary production of FSH and mask an elevation that might otherwise reveal diminished ovarian reserve. Measurement of both FSH and estradiol on cycle day 3 may therefore help decrease the incidence of false-negative testing.

Commonly cited criteria for normal ovarian reserve are:

• early follicular phase FSH, <10 mIU/mL
• estradiol, <80 pg/mL¹

It is extremely important to note, however, that these are general guidelines and that cutoffs are both laboratory- and practice-specific.

FIGURE 2 Monthly and lifetime variations in estradiol and FSH

How 17ß-estradiol and follicle-stimulating hormone levels vary over the menstrual cycle (top) and a woman’s lifetime (bottom).

2 | Clomiphene citrate—more sensitive than FSH testing

Like basal FSH testing, the CCCT is an indirect assessment of ovarian reserve. Unlike FSH testing, the CCCT is provocative. It involves administration of 100 mg of clomiphene citrate (Clomid) on days 5 through 9 of the menstrual cycle, with FSH and estradiol measured on days 3 and 10. Once clomiphene citrate is administered, FSH and LH levels rise, followed by an increase in estradiol and inhibin. Evidence suggests that the smaller follicular cohorts in women with diminished ovarian reserve produce less inhibin-B and estradiol and, therefore, less negative feedback on clomiphene-induced pituitary FSH release.^6,7 The result: persistent elevation of the day 10 FSH value and a positive screen for diminished ovarian reserve.

In some women, day 10 FSH is elevated even after a normal day 3 value. This makes the CCCT more sensitive than basal FSH testing; it can identify women who might go unrecognized if evaluated by day 3 FSH and estradiol levels alone.

More expensive and labor-intensive than the alternatives

Interpretation of the CCCT requires that FSH and estradiol both be assessed on days 3 and 10. An elevated FSH (≥10 mIU/mL) on either day indicates diminished ovarian reserve. As with basal FSH testing, elevated estradiol (≥80 pg/mL) on day 3 is considered abnormal. The day 10 estradiol value of the CCCT reflects whether or not clomiphene citrate was administered appropriately, and should be elevated. However, the significance of the day 10 estradiol level has been debated with respect to its predictive value for pregnancy in infertile populations.⁸

The addition of day 10 FSH assessment improves the sensitivity of the CCCT over basal FSH measurement, but makes it a more expensive and labor-intensive test ( TABLE ).^5,6 The CCCT involves administration of clomiphene citrate, a safe drug (though it can have side effects), and two blood draws instead of one. Nevertheless, both tests are relatively noninvasive, rapid measures of ovarian reserve.

Drawbacks of the tests

Both basal FSH testing and the CCCT are widely used, although support for their ability to predict ovarian reserve in the infertile population has been challenged recently. Newer data demonstrate that these tests are limited in their ability to predict outcome (pregnancy and response to superovulation drugs) in all but a narrow group of patients undergoing IVF. Performance is particularly limited in:

• young women
• women in the general infertility population who are not utilizing IVF.^9-13

Additional drawbacks of basal FSH testing and the CCCT include:

• significant variability of test results from cycle to cycle (intercycle variability)
• limited time frame within which the tests can be performed (intracycle variability).

The basal FSH test and CCCT have high specificity (98% to 99% for each) as an assessment of reproductive performance in infertile women and generate few false-positive results.^5,6 However, the high screen cutoffs that allow for such specificity come at a price: Few women will screen positive, and sensitivity of the tests is low (between 7% and 8% for basal FSH and between 25% and 40% for the CCCT). Such low sensitivity means that many women will not conceive after infertility treatment despite a normal test result.^5,11 Overall, the tests are not highly informative for many women who get tested.

Once abnormal, normal results are meaningless

Once an FSH level or the CCCT has ever been abnormal, the patient has diminished ovarian reserve; normal values in subsequent menstrual cycles do not improve the odds of pregnancy with treatment.¹⁴ This fact can be a significant source of confusion and frustration for patients.

3 | GnRH agonist stimulation —no better than FSH testing

This test was developed in the search for a very sensitive assessment of ovarian reserve. It was designed to uncover subtle abnormalities in pituitary and ovarian dynamics. It involves administering a gonadotropin-releasing hormone (GnRH) agonist such as leuprolide acetate (Lupron) on day 2 or 3 of the menstrual cycle and measuring pituitary and ovarian hormone responses.^5,15

One group of investigators demonstrated a correlation between stimulated estradiol levels and responsiveness during IVF,¹⁶ but other studies have shown that the test does not perform significantly better than day 3 FSH in predicting ovarian reserve.^17,18

The sensitivity of GnRH agonist testing for pregnancy is moderate (32% to 89%); specificity ranges from 79% to 97%.¹⁹

4 | Inhibin-B—not helpful when used alone

This glycoprotein hormone produced by granulosa cells of developing follicles is a direct measure of ovarian reserve when assessed in the early follicular phase of the menstrual cycle.²⁰ Women treated with IVF who have a low inhibin-B level—particularly when using cutoffs below the range of 45–80 pg/mL—have been shown to respond poorly to superovulation and have a lower pregnancy rate than women with high inhibin-B.^21,22 One group of investigators demonstrated that women with clinical evidence of diminished ovarian reserve but a normal FSH level also had low inhibin-B production, suggesting that it may be a more sensitive marker than FSH.²²

Inhibin-B testing involves a simple blood draw. However, the test has been incorporated into clinical assessment of ovarian reserve only to a limited degree, due to the lack of reliable assays and controversy concerning its prognostic value.²³

Because of these limitations, routine testing of serum inhibin-B in isolation of other markers of ovarian reserve is not recommended.

5 | Antral follicle count—good predictor of IVF outcome

Transvaginal ultrasonographic determination of the number of ovarian follicles that measure between 2 mm and 10 mm in diameter in the early follicular phase of the cycle yields the AFC. As a direct marker of the cohort of growing follicles in the early menstrual cycle, the AFC is believed to correlate strongly with the number of primordial follicles present in the ovary and, therefore, ovarian reserve. Total AFCs of less than 5 to 10 are suggestive of diminished ovarian reserve.^24,25

In IVF cycles, AFC has proven to be an accurate predictor of number of oocytes retrieved, risk of cycle cancellation, and odds of conception.^24,25 Some investigators have even suggested that, compared with other markers of ovarian reserve, AFC is the best independent predictor of outcome in IVF cycles.^7,26-27

In a group of normally cycling women with proven fertility, AFC also showed a strong correlation with age, declining slowly until age 37 and more rapidly thereafter.^28,29

AFC sensitivity for pregnancy is moderate and varies widely in published reports (8% to 60%), whereas specificity tends to be higher (33% to 96%).¹⁹

Drawbacks of AFC

• Because of the need to perform transvaginal ultrasonography, AFC is a more invasive and often more expensive test than hormonal biomarkers
• Accurate assessment of AFC requires an experienced sonographer and can be limited in patients who have had pelvic surgery or uterine fibroids and in those who are obese
• Moderate interobserver and intercycle variability of AFC determinations limits its reproducibility^29,30
• As with basal FSH measurement, the intercycle variability of AFC does not correlate well with IVF outcome in individual patients.³⁰

6 | Anti-Müllerian hormone— many advantages

The drawbacks of the tests just described— e.g., intercycle variability, lack of uniform cutoffs, and limited ability to predict IVF outcomes—make the development of more reliable measures of ovarian reserve a priority in reproductive medicine. AMH is a highly promising marker that appears to have many advantages over other tests and may have the greatest power to predict ovarian aging in women of reproductive age.

How it works

AMH is a glycoprotein growth factor and a member of the transforming growth factor-ß superfamily.³¹ It is primarily produced by the pool of early-growing follicles, which are believed to serve as a proxy for the number of primordial follicles in the ovary. The number of primordial follicles at a given point in time represents the ovarian reserve. AMH levels above 0.7 ng/mL are considered normal; values between 0.3 ng/mL and 0.7 ng/mL are consistent with borderline ovarian reserve, according to 2007 data from Reprosource Corp.

AMH has been studied as a marker of ovarian reserve for 6 years, with multiple reports describing declines in levels with age and with diminishing oocyte numbers. It is undetectable at menopause.³²

The age-related decline in AMH is gradual but measurable even in young women, consistently preceding changes in other markers of ovarian reserve such as FSH and inhibin-B.^32-35 The longitudinal changes in AMH have been demonstrated in ovulatory premenopausal women and healthy volunteers with proven fertility.^33,34 In one series of women followed over a mean of 4 years (ages 25 to 46), AMH testing was superior to day 3 FSH, inhibin-B, and AFC in its ability to predict the onset of cycle irregularity and the menopausal transition.³³

Does it predict oocyte quality?

AMH has performed well as a biomarker, comparable in most series to AFC and superior to FSH. AMH levels are strongly correlated with the number of oocytes retrieved during IVF and the odds of cycle cancellation due to poor response^35-41 —but does it accurately characterize oocyte quality, the other element of ovarian reserve?

Some reports have shown a strong association between AMH levels and surrogates of oocyte quality, including fertilization, oocyte morphology, embryo quality, and pregnancy and miscarriage rates,^36-41 but others have not.⁴² Some reports demonstrate a relationship between AMH and some but not all surrogate markers of oocyte quality.⁴⁰

Advantages of AMH

• It demonstrates minimal intracycle variability.^32,43-45 Compared with other markers of ovarian reserve, which must be measured early in the follicular phase of the menstrual cycle, AMH can be assessed at random times, making it a more convenient method for patients and physicians
• It demonstrates minimal intercycle variability^32,34
• AMH levels are not significantly affected by the hormonal changes of pregnancy, oral contraceptive use, or GnRH treatment, and can be measured in these settings.^46,47

Utility of AMH is limited in PCOS and obesity

The ability to use AMH as a marker of ovarian aging in women who have polycystic ovary syndrome (PCOS) and in women who are obese may be limited by the ovulatory dysfunction in these populations. Circulating levels of AMH are higher in women with PCOS than in unaffected women, a finding thought to be indicative of oligo-ovulation and poor follicular development in polycystic ovaries.^48-53

In a recent series investigating AMH levels in women with PCOS, AMH and the degree of insulin resistance were positively correlated, and the AMH level was negatively correlated with the number of menses in a year.⁴⁹ The consistently positive correlation between AMH and PCOS may suggest a future role for this marker as a diagnostic tool.

In obese women who do not have PCOS, AMH production may be lower than in women of normal weight. In a recent series, normally cycling obese women in the later reproductive years were shown to have an AMH level 70% lower than those in women who were not obese.⁵⁴ These differences have not been well studied in younger obese women.

Which test is best?

AMH may be preferable to the other tests to assess ovarian reserve because it can be measured any time during the menstrual cycle or between cycles. AMH measurement is also useful if a woman is taking oral contraceptives or leuprolide acetate because these medications may confound the results of the other test methods. In addition, AMH may be the earliest indicator of decline in ovarian reproductive function. As such, it may highlight cases that merit a search for other causes of infertility and make it possible to treat them in a timely manner.

Elevated AMH may reveal occult PCOS and warn of significant risk of ovarian hyperstimulation prior to ovulation induction with gonadotrophins, so that the clinician can plan smaller doses.

The University of Medicine and Dentistry of New Jersey (UMDNJ) owns a patent relating to the use of anti-Müllerian hormone/Müllerian inhibiting substance for predicting ovarian response in women with infertility. The patent is based in part on work that Dr. Seifer carried out while employed at UMDNJ. In accordance with UMDNJ policy, Dr. Seifer, a named inventor on this patent, assigned his interest in the invention to UMDNJ. UMDNJ has a licensing agreement with Diagnostic Systems Laboratory for the use of the claimed invention. Dr. Seifer receives a portion of the royalties, as determined by UMDNJ policy, that UMDNJ gains from this licensing agreement.

CASE: Borderline test result prompts referral

A 36-year-old nulliparous woman is seen in your office for evaluation after 6 months of infertility. She is ovulatory, and has been using an ovulation-prediction kit to time intercourse. You learn that she had Chlamydia trachomatis infection in the distant past, but elicit no other significant medical or surgical history. She reports that she smoked approximately one pack of cigarettes a day for 15 years but gave up smoking 5 years ago.

You order a hysterosalpingogram, followed by day 3 testing of follicle-stimulating hormone (FSH). The hysterosalpingogram is normal; the FSH level is 7.5 mIU/mL and the estradiol level is 30 pg/mL—both in the normal range.

The patient asks for testing of anti-Müllerian hormone (AMH; also known as Müllerian-inhibiting substance) because she has read that it is a new marker of fertility. The result is 0.5 ng/mL, a borderline value. After reviewing these results, you refer her to a reproductive endocrinologist for further management.

Was the test for AMH indicated? And is this referral appropriate?

The referral is entirely appropriate, even though the patient has not been trying to conceive for a full year. Why? The AMH value suggests that her ovarian reserve is in early decline. She would benefit from evaluation by a subspecialist who can review the entire spectrum of treatments, including aggressive options such as ovulation induction and in vitro fertilization (IVF), to optimize her reproductive success.

This article reviews the various biomarkers available to assess ovarian reserve in women who experience infertility:

• day 3 (basal) FSH
• clomiphene citrate challenge
• gonadotropin-releasing hormone (GnRH) agonist stimulation
• inhibin-B
• antral follicle count (AFC)
• AMH.

The AFC and AMH tend to detect the earliest changes in ovarian reserve, followed, sequentially, by inhibin-B, the clomiphene citrate challenge test (CCCT), and basal FSH.

The tests we describe are used primarily to assess treatment prognosis in infertile women. In time, however, appropriate population screening of ovarian reserve may be feasible to provide many more women with information about their reproductive potential and help them shape their life plan.

What makes a test valuable?

Ovarian reserve describes a woman’s reproductive potential—specifically, the number and quality of oocytes she possesses.¹ Biochemical tests of ovarian reserve emerged during the rise of assisted reproductive technologies (ART) in the late 1980s to predict both responsiveness to superovulation drugs and the odds of pregnancy with treatment.

Ideally, a test that assesses ovarian reserve should be affordable, straightforward, rapidly interpretable, and minimally invasive. It also should be able to detect changes that begin early in reproductive life. To be applicable to large populations of reproductive-age women, it should be of use anytime in the menstrual cycle, and should provide reproducible and highly accurate assessment of the reproductive aging process.

Our ability to offer tests that accurately measure ovarian reserve has a significant impact on women at risk of infertility and early menopause and on those who choose to delay childbearing for personal (nonmedical) reasons. These tests have become increasingly relevant because women are choosing to have their first child at a later age than their counterparts did 20 years ago:

• In 1980, 40% of women having their first baby were younger than 25 years, and only 5% were older than 35
• In 2000, 25% of women were younger than 25 when their first child was born, and 15% were older than 35.

Who should be tested?

Ovarian reserve is a complex clinical phenomenon that is influenced by age, genetics, and environmental variables. The decline in a woman’s ovarian reserve over time is irreversible; the trajectory of this decline is fundamental to the odds of fertility with age and the timing of the menopausal transition. At present, the markers used most often in clinical practice have some utility but also suffer from several drawbacks ( TABLE ).

For the general practitioner performing an infertility evaluation, we recommend focusing on the following groups of women for ovarian reserve testing:

• women over 30 years of age
• women with a history of exposure to a confirmed gonadotoxin, i.e., tobacco smoke, chemotherapy, radiation therapy
• women with a strong family history of early menopause or premature ovarian failure
• women who have had extensive ovarian surgery, i.e., cystectomy and unilateral oophorectomy.

Testing tends to have the highest yield in these groups. Women who have abnormal results should be referred to a reproductive endocrinologist for further evaluation and treatment.

The six tests are described below.

TABLE

How six markers of ovarian reserve stack up

1 | Basal FSH—widely used but only moderately informative

Day 3 FSH and the CCCT are the most widely used measures of ovarian reserve in ART practice. The use of early follicular-phase FSH as a marker of ovarian reserve and fertility was proposed 20 years ago with the emergence of IVF.^2-4 The test is an indirect assessment of ovarian reserve in that it measures pituitary production of FSH in response to feedback from ovarian hormones. Estradiol and inhibin-B reach a nadir early in the menstrual cycle; measuring FSH on day 3 offers a glimpse of the functioning of the hypothalamic–pituitary–ovarian axis before ovarian hormone levels rise later in the cycle ( FIGURE 1 ).^5,6

FIGURE 1 The HPO axis

The FSH level opens a window onto the function of the hypothalamic–pituitary–ovarian axis before ovarian hormone levels rise in the cycle. Women who have normal ovarian reserve have sufficient ovarian hormone production early in the menstrual cycle to maintain FSH levels within the normal range. Conversely, a “monotropic” elevation in FSH—one that is unaccompanied by a rise in luteinizing hormone (LH)—reflects poor hormone production from an aging pool of ovarian follicles and disinhibition of FSH production.^5,6

FSH measurements are typically combined with estradiol to enhance the sensitivity of testing ( FIGURE 2, ). Premature elevations of estradiol early in the follicular phase are driven by rising FSH levels in women with declining ovarian reserve. Abnormally elevated estrogen levels then feed back negatively on pituitary production of FSH and mask an elevation that might otherwise reveal diminished ovarian reserve. Measurement of both FSH and estradiol on cycle day 3 may therefore help decrease the incidence of false-negative testing.

Commonly cited criteria for normal ovarian reserve are:

• early follicular phase FSH, <10 mIU/mL
• estradiol, <80 pg/mL¹

It is extremely important to note, however, that these are general guidelines and that cutoffs are both laboratory- and practice-specific.

FIGURE 2 Monthly and lifetime variations in estradiol and FSH

How 17ß-estradiol and follicle-stimulating hormone levels vary over the menstrual cycle (top) and a woman’s lifetime (bottom).

2 | Clomiphene citrate—more sensitive than FSH testing

Like basal FSH testing, the CCCT is an indirect assessment of ovarian reserve. Unlike FSH testing, the CCCT is provocative. It involves administration of 100 mg of clomiphene citrate (Clomid) on days 5 through 9 of the menstrual cycle, with FSH and estradiol measured on days 3 and 10. Once clomiphene citrate is administered, FSH and LH levels rise, followed by an increase in estradiol and inhibin. Evidence suggests that the smaller follicular cohorts in women with diminished ovarian reserve produce less inhibin-B and estradiol and, therefore, less negative feedback on clomiphene-induced pituitary FSH release.^6,7 The result: persistent elevation of the day 10 FSH value and a positive screen for diminished ovarian reserve.

In some women, day 10 FSH is elevated even after a normal day 3 value. This makes the CCCT more sensitive than basal FSH testing; it can identify women who might go unrecognized if evaluated by day 3 FSH and estradiol levels alone.

More expensive and labor-intensive than the alternatives

Interpretation of the CCCT requires that FSH and estradiol both be assessed on days 3 and 10. An elevated FSH (≥10 mIU/mL) on either day indicates diminished ovarian reserve. As with basal FSH testing, elevated estradiol (≥80 pg/mL) on day 3 is considered abnormal. The day 10 estradiol value of the CCCT reflects whether or not clomiphene citrate was administered appropriately, and should be elevated. However, the significance of the day 10 estradiol level has been debated with respect to its predictive value for pregnancy in infertile populations.⁸

The addition of day 10 FSH assessment improves the sensitivity of the CCCT over basal FSH measurement, but makes it a more expensive and labor-intensive test ( TABLE ).^5,6 The CCCT involves administration of clomiphene citrate, a safe drug (though it can have side effects), and two blood draws instead of one. Nevertheless, both tests are relatively noninvasive, rapid measures of ovarian reserve.

Drawbacks of the tests

Both basal FSH testing and the CCCT are widely used, although support for their ability to predict ovarian reserve in the infertile population has been challenged recently. Newer data demonstrate that these tests are limited in their ability to predict outcome (pregnancy and response to superovulation drugs) in all but a narrow group of patients undergoing IVF. Performance is particularly limited in:

• young women
• women in the general infertility population who are not utilizing IVF.^9-13

Additional drawbacks of basal FSH testing and the CCCT include:

• significant variability of test results from cycle to cycle (intercycle variability)
• limited time frame within which the tests can be performed (intracycle variability).

The basal FSH test and CCCT have high specificity (98% to 99% for each) as an assessment of reproductive performance in infertile women and generate few false-positive results.^5,6 However, the high screen cutoffs that allow for such specificity come at a price: Few women will screen positive, and sensitivity of the tests is low (between 7% and 8% for basal FSH and between 25% and 40% for the CCCT). Such low sensitivity means that many women will not conceive after infertility treatment despite a normal test result.^5,11 Overall, the tests are not highly informative for many women who get tested.

Once abnormal, normal results are meaningless

Once an FSH level or the CCCT has ever been abnormal, the patient has diminished ovarian reserve; normal values in subsequent menstrual cycles do not improve the odds of pregnancy with treatment.¹⁴ This fact can be a significant source of confusion and frustration for patients.

3 | GnRH agonist stimulation —no better than FSH testing

This test was developed in the search for a very sensitive assessment of ovarian reserve. It was designed to uncover subtle abnormalities in pituitary and ovarian dynamics. It involves administering a gonadotropin-releasing hormone (GnRH) agonist such as leuprolide acetate (Lupron) on day 2 or 3 of the menstrual cycle and measuring pituitary and ovarian hormone responses.^5,15

One group of investigators demonstrated a correlation between stimulated estradiol levels and responsiveness during IVF,¹⁶ but other studies have shown that the test does not perform significantly better than day 3 FSH in predicting ovarian reserve.^17,18

The sensitivity of GnRH agonist testing for pregnancy is moderate (32% to 89%); specificity ranges from 79% to 97%.¹⁹

4 | Inhibin-B—not helpful when used alone

This glycoprotein hormone produced by granulosa cells of developing follicles is a direct measure of ovarian reserve when assessed in the early follicular phase of the menstrual cycle.²⁰ Women treated with IVF who have a low inhibin-B level—particularly when using cutoffs below the range of 45–80 pg/mL—have been shown to respond poorly to superovulation and have a lower pregnancy rate than women with high inhibin-B.^21,22 One group of investigators demonstrated that women with clinical evidence of diminished ovarian reserve but a normal FSH level also had low inhibin-B production, suggesting that it may be a more sensitive marker than FSH.²²

Inhibin-B testing involves a simple blood draw. However, the test has been incorporated into clinical assessment of ovarian reserve only to a limited degree, due to the lack of reliable assays and controversy concerning its prognostic value.²³

Because of these limitations, routine testing of serum inhibin-B in isolation of other markers of ovarian reserve is not recommended.

5 | Antral follicle count—good predictor of IVF outcome

Transvaginal ultrasonographic determination of the number of ovarian follicles that measure between 2 mm and 10 mm in diameter in the early follicular phase of the cycle yields the AFC. As a direct marker of the cohort of growing follicles in the early menstrual cycle, the AFC is believed to correlate strongly with the number of primordial follicles present in the ovary and, therefore, ovarian reserve. Total AFCs of less than 5 to 10 are suggestive of diminished ovarian reserve.^24,25

In IVF cycles, AFC has proven to be an accurate predictor of number of oocytes retrieved, risk of cycle cancellation, and odds of conception.^24,25 Some investigators have even suggested that, compared with other markers of ovarian reserve, AFC is the best independent predictor of outcome in IVF cycles.^7,26-27

In a group of normally cycling women with proven fertility, AFC also showed a strong correlation with age, declining slowly until age 37 and more rapidly thereafter.^28,29

AFC sensitivity for pregnancy is moderate and varies widely in published reports (8% to 60%), whereas specificity tends to be higher (33% to 96%).¹⁹

Drawbacks of AFC

• Because of the need to perform transvaginal ultrasonography, AFC is a more invasive and often more expensive test than hormonal biomarkers
• Accurate assessment of AFC requires an experienced sonographer and can be limited in patients who have had pelvic surgery or uterine fibroids and in those who are obese
• Moderate interobserver and intercycle variability of AFC determinations limits its reproducibility^29,30
• As with basal FSH measurement, the intercycle variability of AFC does not correlate well with IVF outcome in individual patients.³⁰

6 | Anti-Müllerian hormone— many advantages

The drawbacks of the tests just described— e.g., intercycle variability, lack of uniform cutoffs, and limited ability to predict IVF outcomes—make the development of more reliable measures of ovarian reserve a priority in reproductive medicine. AMH is a highly promising marker that appears to have many advantages over other tests and may have the greatest power to predict ovarian aging in women of reproductive age.

How it works

AMH is a glycoprotein growth factor and a member of the transforming growth factor-ß superfamily.³¹ It is primarily produced by the pool of early-growing follicles, which are believed to serve as a proxy for the number of primordial follicles in the ovary. The number of primordial follicles at a given point in time represents the ovarian reserve. AMH levels above 0.7 ng/mL are considered normal; values between 0.3 ng/mL and 0.7 ng/mL are consistent with borderline ovarian reserve, according to 2007 data from Reprosource Corp.

AMH has been studied as a marker of ovarian reserve for 6 years, with multiple reports describing declines in levels with age and with diminishing oocyte numbers. It is undetectable at menopause.³²

The age-related decline in AMH is gradual but measurable even in young women, consistently preceding changes in other markers of ovarian reserve such as FSH and inhibin-B.^32-35 The longitudinal changes in AMH have been demonstrated in ovulatory premenopausal women and healthy volunteers with proven fertility.^33,34 In one series of women followed over a mean of 4 years (ages 25 to 46), AMH testing was superior to day 3 FSH, inhibin-B, and AFC in its ability to predict the onset of cycle irregularity and the menopausal transition.³³

Does it predict oocyte quality?

AMH has performed well as a biomarker, comparable in most series to AFC and superior to FSH. AMH levels are strongly correlated with the number of oocytes retrieved during IVF and the odds of cycle cancellation due to poor response^35-41 —but does it accurately characterize oocyte quality, the other element of ovarian reserve?

Some reports have shown a strong association between AMH levels and surrogates of oocyte quality, including fertilization, oocyte morphology, embryo quality, and pregnancy and miscarriage rates,^36-41 but others have not.⁴² Some reports demonstrate a relationship between AMH and some but not all surrogate markers of oocyte quality.⁴⁰

Advantages of AMH

• It demonstrates minimal intracycle variability.^32,43-45 Compared with other markers of ovarian reserve, which must be measured early in the follicular phase of the menstrual cycle, AMH can be assessed at random times, making it a more convenient method for patients and physicians
• It demonstrates minimal intercycle variability^32,34
• AMH levels are not significantly affected by the hormonal changes of pregnancy, oral contraceptive use, or GnRH treatment, and can be measured in these settings.^46,47

Utility of AMH is limited in PCOS and obesity

The ability to use AMH as a marker of ovarian aging in women who have polycystic ovary syndrome (PCOS) and in women who are obese may be limited by the ovulatory dysfunction in these populations. Circulating levels of AMH are higher in women with PCOS than in unaffected women, a finding thought to be indicative of oligo-ovulation and poor follicular development in polycystic ovaries.^48-53

In a recent series investigating AMH levels in women with PCOS, AMH and the degree of insulin resistance were positively correlated, and the AMH level was negatively correlated with the number of menses in a year.⁴⁹ The consistently positive correlation between AMH and PCOS may suggest a future role for this marker as a diagnostic tool.

In obese women who do not have PCOS, AMH production may be lower than in women of normal weight. In a recent series, normally cycling obese women in the later reproductive years were shown to have an AMH level 70% lower than those in women who were not obese.⁵⁴ These differences have not been well studied in younger obese women.

Which test is best?

AMH may be preferable to the other tests to assess ovarian reserve because it can be measured any time during the menstrual cycle or between cycles. AMH measurement is also useful if a woman is taking oral contraceptives or leuprolide acetate because these medications may confound the results of the other test methods. In addition, AMH may be the earliest indicator of decline in ovarian reproductive function. As such, it may highlight cases that merit a search for other causes of infertility and make it possible to treat them in a timely manner.

Elevated AMH may reveal occult PCOS and warn of significant risk of ovarian hyperstimulation prior to ovulation induction with gonadotrophins, so that the clinician can plan smaller doses.

The author has no financial relationships relevant to this article.

CASE: Inadvertent ureteral transection

A gynecologic surgeon operates via Pfannenstiel incision to remove a 12-cm complex left adnexal mass from a 36-year-old obese woman. When she discovers that the mass is densely adherent to the pelvic peritoneum, the surgeon incises the peritoneum lateral to the mass and opens the retroperitoneal space. However, the size and relative immobility of the mass, coupled with the low transverse incision, impair visualization of retroperitoneal structures.

The surgeon clamps and divides the ovarian vessels above the mass but, afterward, suspects that the ureter has been transected and that its ends are included within the clamps. She separates the ovarian vessels above the clamp and ligates them, at which time transection of the ureter is confirmed.

How should she proceed?

The ureter is intimately associated with the female internal genitalia in a way that challenges the gynecologic surgeon to avoid it. In a small percentage of cases involving surgical extirpation in a woman who has severe pelvic pathology, ureteral injury may be inevitable.

Several variables predispose a patient to ureteral injury, including limited exposure, as in the opening case. Others include distorted anatomy of the urinary tract relative to internal genitalia and operations that require extensive resection of pelvic tissues.

This article describes:

• prevention and intraoperative recognition of ureteral injury during gynecologic surgery
• management of intraoperatively recognized ureteral injury.

Maintain a high index of suspicion

The surgeon in the opening case has already taken the first and most important step in ensuring a good outcome: She suspected ureteral injury. In high-risk situations, intraoperative recognition of ureteral injury is more likely when the operative field is inspected thoroughly during and at the conclusion of the surgical procedure.

In a high-risk case, the combined use of intravenous indigo carmine, careful inspection of the operative field, cystoscopy, and ureteral dissection is recommended and should be routine.

Common sites of injury

During gynecologic surgery, the ureter is susceptible to injury along its entire course through the pelvis (see “The ureter takes a course fraught with hazard,”).

During adnexectomy, the gonadal vessels are generally ligated 2 to 3 cm above the adnexa. The ureter lies in close proximity to these vessels and may inadvertently be included in the ligation.

During hysterectomy, the ureter is susceptible to injury as it passes through the parametrium a short distance from the uterus and vaginal fornix.

Sutures placed in the posterior lateral cul de sac during prolapse surgery lie near the midpelvic ureter, and sutures placed during vaginal cuff closure, anterior colporrhaphy, and retropubic urethropexy are in close proximity to the trigonal portion of the ureter.

The ureter takes a course fraught with hazard

The ureter extends from the renal pelvis to the bladder, with a length that ranges from 25 to 30 cm, depending on the patient’s height. It crosses the pelvic brim near the bifurcation of the common iliac artery, where it becomes the “pelvic” ureter. The abdominal and pelvic portions of the ureter are approximately equal in length.

ILLUSTRATIONS BY ROB FLEWELL FOR OBG MANAGEMENT

The blood supply of the ureter derives from branches of the major arterial system of the lower abdomen and pelvis. These branches reach the medial aspect of the abdominal ureter and the lateral side of the pelvic ureter to form an anastomotic vascular network protected by an adventitial layer surrounding the ureter.

The ureter is attached to the posterior lateral pelvic peritoneum running dorsal to ovarian vessels. At the midpelvis, it separates from the peritoneum to pierce the base of the broad ligament underneath the uterine artery. At this point, the ureter is about 1.5 to 2 cm lateral to the uterus and curves medially and ventrally, tunneling through the cardinal and vesicovaginal ligaments to enter the bladder trigone.

Risky procedures

In gynecologic surgery, ureteral injury occurs most often during abdominal hysterectomy—probably because of how frequently this operation is performed and the range of pathology managed. The incidence of ureteral injury is much higher during abdominal hysterectomy than vaginal hysterectomy.^1-4

Laparoscopic hysterectomy also has been associated with a higher incidence of ureteral injury, especially in the early phase of training.^5,6 Possible explanations include:

• greater difficulty identifying the ureter
• a steeper learning curve
• more frequent use of energy to hemostatically divide pedicles, with the potential for thermal injury
• less traction–countertraction, resulting in dissection closer to the ureter
• management of complex pathology.

Although the overall incidence of ureteral injury during adnexectomy is low, it is probably much higher in women undergoing this procedure after a previous hysterectomy or in the presence of complex adnexal pathology.

When injury is likely

Compromised exposure, distorted anatomy, and certain procedures can heighten the risk of ureteral injury. Large tumors may limit the ability of the surgeon to visualize or palpate the ureter (FIGURE 1). Extensive adhesions may cause similar difficulties, and a small incision or obesity may hinder identification of pelvic sidewall structures.

A number of pathologic conditions can distort the anatomy of the ureter, especially as it relates to the female genital tract:

• Malignancies such as ovarian cancer often encroach on and occasionally encase the ureter
• Pelvic inflammatory disease, endometriosis, and a history of surgery or pelvic radiotherapy can retract and encase the ureter toward the gynecologic tract
• Some masses expand against the lower ureter, such as cervical or broad-ligament leiomyomata or placenta previa with accreta
• During vaginal hysterectomy for complete uterine prolapse, the ureters frequently extend beyond the introitus well within the operative field
• Congenital anomalies of the ureter or hydroureter can also cause distortion.

Even in the presence of relatively normal anatomy, certain procedures predispose the ureter to injury. For example, radical hysterectomy involves the almost complete separation of the pelvic ureter from the gynecologic tract and its surrounding soft tissue. When pelvic pathology is significant, the plane of dissection will always be near the ureter.

FIGURE 1 Access to the ureter is obstructed, putting it in jeopardy

Large tumors may limit the ability of the surgeon to visualize or palpate the ureter.

Prevention is the best strategy

At least 50% of ureteral injuries reported during gynecologic surgery have occurred in the absence of a recognizable risk factor.^2,7 Nevertheless, knowledge of anatomy and the ability to recognize situations in which there is an elevated risk for ureteral injury will best enable the surgeon to prevent such injury.

When a high-risk situation is encountered, critical preventive steps include:

• adequate exposure
• competent assistance
• exposure of the path of the ureter through the planned course of dissection. Dissecting the ureter beyond this area is usually unnecessary and may itself cause injury.

Skip preoperative IVP in most cases

The vast majority of women who undergo gynecologic surgery do not benefit from preoperative intravenous pyelography (IVP). This measure does not appear to reduce the likelihood of ureteral injury, even in the face of obvious gynecologic disease. However, preoperative identification of obvious ureteral involvement by the disease process is useful. In such cases, the plane of dissection will probably lie closer to the ureter. One of the goals of surgery will then be to clear the urinary tract from the affected area.

When there is a high index of suspicion of an abnormality such as obstruction, intrinsic ureteral endometriosis, or congenital anomaly, preoperative IVP is indicated.

A stent may be helpful in some cases

Ureteral stents are sometimes placed in order to aid in identification and dissection of the ureters during surgery. Some authors of reports on this topic, including Hoffman, believe that stents are useful in certain situations, such as excision of an ovarian remnant, radical vaginal hysterectomy, and when pelvic organs are encased by malignant ovarian tumors. However, stents do not clearly reduce the risk of injury and, in some cases, may increase the risk by providing a false sense of security and predisposing the ureter to adventitial injury during difficult dissection.

Anticipate the effects of disease

The surgeon must have a thorough knowledge of the gynecologic disease process as it relates to surgery involving the urinary tract. For example, an ovarian remnant will almost always be somewhat densely adherent to the pelvic ureter. When severe endometriosis involves the posterior leaf of the broad ligament, the ureter will often be fibrotically retracted toward the operative field.

Certain procedures have special challenges. During resection of adnexa, for example, it is important that the ureter be identified in the retroperitoneum before the ovarian vessels are ligated. During hysterectomy, soft tissues that contain the bladder and ureters should be mobilized caudally and laterally, respectively, creating a U-shaped region (“U” for urinary tract, FIGURE 2) to which the surgeon must limit dissection.

FIGURE 2 During hysterectomy, mobilize the bladder and ureter

Mobilize the soft tissues that contain the bladder and ureters caudally and laterally, respectively, creating a U-shaped region. During division of the paracervical tissues, the surgeon must remain within this region.

Intraoperative detection

Two main types of ureteral injury occur during gynecologic surgery: transection and destruction. The latter includes ligation, crushing, devascularization, and thermal injury.

Intraoperative detection of ureteral injury is more likely when the surgeon recognizes at the outset that the operation places the ureter at increased risk. When dissection has been difficult or complicated for any reason, be concerned about possible injury.

In general, ureteral injury is first recognized by careful inspection of the surgical field. Begin by instilling 5 ml of indigo carmine intravenously. Once the dye begins to appear in the Foley catheter, inspect the area of dissection under a small amount of irrigation fluid, looking for extravasation of dye that indicates partial or complete transection.

If no injury is identified, cystoscopy is the next step. I perform all major abdominal operations with the patient in the low lithotomy position, which provides easy access to the perineum. Cystoscopic identification of urine jetting from both ureteral orifices confirms patency. When only wisps of dye are observed, it is likely that the ureter in question has been partially occluded (e.g., by acute angulation). Failure of any urine to appear from one of the orifices highly suggests injury to that ureter.

During inspection of the operative field, attempt to pass a ureteral stent into the affected orifice. If the stent passes easily and dyed urine is seen to drip freely from it, look for possible angulation of the ureter. If you find none, remove the stent and inspect the orifice again for jetting urine.

If the ureteral stent will move only a few centimeters into the ureteral orifice, ligation (with or without transection) is likely. In this case, leave the stent in place. If the operative site is readily accessible, dissect the applicable area to identify the problem. Depending on the circumstances, you may wish to infuse dye through the stent to aid in operative identification or radiographic evaluation.

Intraoperative IVP may be useful, especially when cystoscopy is unavailable.

Fundamentals of repair

Repair of major injury to the pelvic ureter is generally best accomplished by ureteroneocystostomy or, in selected cases involving injury to the proximal pelvic ureter, by ureteroureterostomy.

When intraoperatively recognized injury to the pelvic ureter appears to be minor, it can be managed by placing a ureteral stent and a closed-suction pelvic drain. Also consider wrapping the injured area with vascularized tissue such as perivesical fat. Minor lacerations can be closed perpendicular to the axis of the ureter using interrupted 4-0 delayed absorbable suture.

Most injuries to the pelvic ureter are optimally managed by ureteroneocystostomy (FIGURE 3). When a significant portion of the pelvic ureter has been lost, ureteroneocystostomy usually requires a combination of:

• extensive mobilization of the bladder
• conservative mobilization of the ureter
• elongation of the bladder
• psoas hitch.

When necessary, mobilization of the kidney with suturing of the caudal perinephric fascia to the psoas muscle will bridge an additional 2- to 3-cm gap.

Major injury to the distal half of the pelvic ureter is repaired using straightforward ureteroneocystostomy.

When there is no significant pelvic disease and the distal ureter is healthy, injury to the proximal pelvic ureter during division of the ovarian vessels may be repaired via ureteroureterostomy. If the ureteral ends will be anastomosed on tension or there is any question about the integrity of the distal portion of the ureter, as when extensive distal ureterolysis has been necessary, consider ureteroneocystostomy.

FIGURE 3 When the distal ureter is injured

Most injuries to the pelvic ureter are managed optimally by ureteroneocystostomy.

Postoperative management

After repair of a ureteral injury, leave a closed-suction pelvic drain in place for 2 to 3 days so that any major urinary leak can be detected; it also enhances spontaneous closure and helps prevent potentially infected fluid from accumulating in the region of anastomosis.

The cystotomy performed during ureteroneocystostomy generally heals quickly with a low risk of complications.

Leave a large-bore (20 or 22 French) urethral Foley catheter in place for 2 weeks.

I recommend that a 6 French double-J ureteral stent be left in place for 6 weeks. Potential benefits of the stent include:

• prevention of stricture
• stabilization and immobilization of the ureter during healing
• reduced risk of extravasation of urine
• reduced risk of angulation of the ureter
• isolation of the repair from infection, retroperitoneal fibrosis, and cancer.

I perform IVP approximately 1 week after stent removal to ensure ureteral patency.

CASE RESOLVED

Exposure is improved by widening the incision and dividing the tendonous insertions of the rectus abdominus muscles. The surgeon then removes the mass, preserving the distal ureter, which is estimated to be 12 cm in length and to have intact adventitia.

The surgeon performs a double-spatulated end-to-end ureteroureterostomy over a 6 French double-J ureteral stent that has been passed proximally into the renal pelvis and distally into the bladder. The stent is removed 6 weeks postoperatively, and an IVP the following week demonstrates excellent patency.

The author has no financial relationships relevant to this article.

CASE: Inadvertent ureteral transection

A gynecologic surgeon operates via Pfannenstiel incision to remove a 12-cm complex left adnexal mass from a 36-year-old obese woman. When she discovers that the mass is densely adherent to the pelvic peritoneum, the surgeon incises the peritoneum lateral to the mass and opens the retroperitoneal space. However, the size and relative immobility of the mass, coupled with the low transverse incision, impair visualization of retroperitoneal structures.

The surgeon clamps and divides the ovarian vessels above the mass but, afterward, suspects that the ureter has been transected and that its ends are included within the clamps. She separates the ovarian vessels above the clamp and ligates them, at which time transection of the ureter is confirmed.

How should she proceed?

The ureter is intimately associated with the female internal genitalia in a way that challenges the gynecologic surgeon to avoid it. In a small percentage of cases involving surgical extirpation in a woman who has severe pelvic pathology, ureteral injury may be inevitable.

Several variables predispose a patient to ureteral injury, including limited exposure, as in the opening case. Others include distorted anatomy of the urinary tract relative to internal genitalia and operations that require extensive resection of pelvic tissues.

This article describes:

• prevention and intraoperative recognition of ureteral injury during gynecologic surgery
• management of intraoperatively recognized ureteral injury.

Maintain a high index of suspicion

The surgeon in the opening case has already taken the first and most important step in ensuring a good outcome: She suspected ureteral injury. In high-risk situations, intraoperative recognition of ureteral injury is more likely when the operative field is inspected thoroughly during and at the conclusion of the surgical procedure.

In a high-risk case, the combined use of intravenous indigo carmine, careful inspection of the operative field, cystoscopy, and ureteral dissection is recommended and should be routine.

Common sites of injury

During gynecologic surgery, the ureter is susceptible to injury along its entire course through the pelvis (see “The ureter takes a course fraught with hazard,”).

During adnexectomy, the gonadal vessels are generally ligated 2 to 3 cm above the adnexa. The ureter lies in close proximity to these vessels and may inadvertently be included in the ligation.

During hysterectomy, the ureter is susceptible to injury as it passes through the parametrium a short distance from the uterus and vaginal fornix.

Sutures placed in the posterior lateral cul de sac during prolapse surgery lie near the midpelvic ureter, and sutures placed during vaginal cuff closure, anterior colporrhaphy, and retropubic urethropexy are in close proximity to the trigonal portion of the ureter.

The ureter takes a course fraught with hazard

The ureter extends from the renal pelvis to the bladder, with a length that ranges from 25 to 30 cm, depending on the patient’s height. It crosses the pelvic brim near the bifurcation of the common iliac artery, where it becomes the “pelvic” ureter. The abdominal and pelvic portions of the ureter are approximately equal in length.

ILLUSTRATIONS BY ROB FLEWELL FOR OBG MANAGEMENT

The blood supply of the ureter derives from branches of the major arterial system of the lower abdomen and pelvis. These branches reach the medial aspect of the abdominal ureter and the lateral side of the pelvic ureter to form an anastomotic vascular network protected by an adventitial layer surrounding the ureter.

The ureter is attached to the posterior lateral pelvic peritoneum running dorsal to ovarian vessels. At the midpelvis, it separates from the peritoneum to pierce the base of the broad ligament underneath the uterine artery. At this point, the ureter is about 1.5 to 2 cm lateral to the uterus and curves medially and ventrally, tunneling through the cardinal and vesicovaginal ligaments to enter the bladder trigone.

Risky procedures

In gynecologic surgery, ureteral injury occurs most often during abdominal hysterectomy—probably because of how frequently this operation is performed and the range of pathology managed. The incidence of ureteral injury is much higher during abdominal hysterectomy than vaginal hysterectomy.^1-4

Laparoscopic hysterectomy also has been associated with a higher incidence of ureteral injury, especially in the early phase of training.^5,6 Possible explanations include:

• greater difficulty identifying the ureter
• a steeper learning curve
• more frequent use of energy to hemostatically divide pedicles, with the potential for thermal injury
• less traction–countertraction, resulting in dissection closer to the ureter
• management of complex pathology.

Although the overall incidence of ureteral injury during adnexectomy is low, it is probably much higher in women undergoing this procedure after a previous hysterectomy or in the presence of complex adnexal pathology.

When injury is likely

Compromised exposure, distorted anatomy, and certain procedures can heighten the risk of ureteral injury. Large tumors may limit the ability of the surgeon to visualize or palpate the ureter (FIGURE 1). Extensive adhesions may cause similar difficulties, and a small incision or obesity may hinder identification of pelvic sidewall structures.

A number of pathologic conditions can distort the anatomy of the ureter, especially as it relates to the female genital tract:

• Malignancies such as ovarian cancer often encroach on and occasionally encase the ureter
• Pelvic inflammatory disease, endometriosis, and a history of surgery or pelvic radiotherapy can retract and encase the ureter toward the gynecologic tract
• Some masses expand against the lower ureter, such as cervical or broad-ligament leiomyomata or placenta previa with accreta
• During vaginal hysterectomy for complete uterine prolapse, the ureters frequently extend beyond the introitus well within the operative field
• Congenital anomalies of the ureter or hydroureter can also cause distortion.

Even in the presence of relatively normal anatomy, certain procedures predispose the ureter to injury. For example, radical hysterectomy involves the almost complete separation of the pelvic ureter from the gynecologic tract and its surrounding soft tissue. When pelvic pathology is significant, the plane of dissection will always be near the ureter.

FIGURE 1 Access to the ureter is obstructed, putting it in jeopardy

Large tumors may limit the ability of the surgeon to visualize or palpate the ureter.

Prevention is the best strategy

At least 50% of ureteral injuries reported during gynecologic surgery have occurred in the absence of a recognizable risk factor.^2,7 Nevertheless, knowledge of anatomy and the ability to recognize situations in which there is an elevated risk for ureteral injury will best enable the surgeon to prevent such injury.

When a high-risk situation is encountered, critical preventive steps include:

• adequate exposure
• competent assistance
• exposure of the path of the ureter through the planned course of dissection. Dissecting the ureter beyond this area is usually unnecessary and may itself cause injury.

Skip preoperative IVP in most cases

The vast majority of women who undergo gynecologic surgery do not benefit from preoperative intravenous pyelography (IVP). This measure does not appear to reduce the likelihood of ureteral injury, even in the face of obvious gynecologic disease. However, preoperative identification of obvious ureteral involvement by the disease process is useful. In such cases, the plane of dissection will probably lie closer to the ureter. One of the goals of surgery will then be to clear the urinary tract from the affected area.

When there is a high index of suspicion of an abnormality such as obstruction, intrinsic ureteral endometriosis, or congenital anomaly, preoperative IVP is indicated.

A stent may be helpful in some cases

Ureteral stents are sometimes placed in order to aid in identification and dissection of the ureters during surgery. Some authors of reports on this topic, including Hoffman, believe that stents are useful in certain situations, such as excision of an ovarian remnant, radical vaginal hysterectomy, and when pelvic organs are encased by malignant ovarian tumors. However, stents do not clearly reduce the risk of injury and, in some cases, may increase the risk by providing a false sense of security and predisposing the ureter to adventitial injury during difficult dissection.

Anticipate the effects of disease

The surgeon must have a thorough knowledge of the gynecologic disease process as it relates to surgery involving the urinary tract. For example, an ovarian remnant will almost always be somewhat densely adherent to the pelvic ureter. When severe endometriosis involves the posterior leaf of the broad ligament, the ureter will often be fibrotically retracted toward the operative field.

Certain procedures have special challenges. During resection of adnexa, for example, it is important that the ureter be identified in the retroperitoneum before the ovarian vessels are ligated. During hysterectomy, soft tissues that contain the bladder and ureters should be mobilized caudally and laterally, respectively, creating a U-shaped region (“U” for urinary tract, FIGURE 2) to which the surgeon must limit dissection.

FIGURE 2 During hysterectomy, mobilize the bladder and ureter

Mobilize the soft tissues that contain the bladder and ureters caudally and laterally, respectively, creating a U-shaped region. During division of the paracervical tissues, the surgeon must remain within this region.

Intraoperative detection

Two main types of ureteral injury occur during gynecologic surgery: transection and destruction. The latter includes ligation, crushing, devascularization, and thermal injury.

Intraoperative detection of ureteral injury is more likely when the surgeon recognizes at the outset that the operation places the ureter at increased risk. When dissection has been difficult or complicated for any reason, be concerned about possible injury.

In general, ureteral injury is first recognized by careful inspection of the surgical field. Begin by instilling 5 ml of indigo carmine intravenously. Once the dye begins to appear in the Foley catheter, inspect the area of dissection under a small amount of irrigation fluid, looking for extravasation of dye that indicates partial or complete transection.

If no injury is identified, cystoscopy is the next step. I perform all major abdominal operations with the patient in the low lithotomy position, which provides easy access to the perineum. Cystoscopic identification of urine jetting from both ureteral orifices confirms patency. When only wisps of dye are observed, it is likely that the ureter in question has been partially occluded (e.g., by acute angulation). Failure of any urine to appear from one of the orifices highly suggests injury to that ureter.

During inspection of the operative field, attempt to pass a ureteral stent into the affected orifice. If the stent passes easily and dyed urine is seen to drip freely from it, look for possible angulation of the ureter. If you find none, remove the stent and inspect the orifice again for jetting urine.

If the ureteral stent will move only a few centimeters into the ureteral orifice, ligation (with or without transection) is likely. In this case, leave the stent in place. If the operative site is readily accessible, dissect the applicable area to identify the problem. Depending on the circumstances, you may wish to infuse dye through the stent to aid in operative identification or radiographic evaluation.

Intraoperative IVP may be useful, especially when cystoscopy is unavailable.

Fundamentals of repair

Repair of major injury to the pelvic ureter is generally best accomplished by ureteroneocystostomy or, in selected cases involving injury to the proximal pelvic ureter, by ureteroureterostomy.

When intraoperatively recognized injury to the pelvic ureter appears to be minor, it can be managed by placing a ureteral stent and a closed-suction pelvic drain. Also consider wrapping the injured area with vascularized tissue such as perivesical fat. Minor lacerations can be closed perpendicular to the axis of the ureter using interrupted 4-0 delayed absorbable suture.

Most injuries to the pelvic ureter are optimally managed by ureteroneocystostomy (FIGURE 3). When a significant portion of the pelvic ureter has been lost, ureteroneocystostomy usually requires a combination of:

• extensive mobilization of the bladder
• conservative mobilization of the ureter
• elongation of the bladder
• psoas hitch.

When necessary, mobilization of the kidney with suturing of the caudal perinephric fascia to the psoas muscle will bridge an additional 2- to 3-cm gap.

Major injury to the distal half of the pelvic ureter is repaired using straightforward ureteroneocystostomy.

When there is no significant pelvic disease and the distal ureter is healthy, injury to the proximal pelvic ureter during division of the ovarian vessels may be repaired via ureteroureterostomy. If the ureteral ends will be anastomosed on tension or there is any question about the integrity of the distal portion of the ureter, as when extensive distal ureterolysis has been necessary, consider ureteroneocystostomy.

FIGURE 3 When the distal ureter is injured

Most injuries to the pelvic ureter are managed optimally by ureteroneocystostomy.

Postoperative management

After repair of a ureteral injury, leave a closed-suction pelvic drain in place for 2 to 3 days so that any major urinary leak can be detected; it also enhances spontaneous closure and helps prevent potentially infected fluid from accumulating in the region of anastomosis.

The cystotomy performed during ureteroneocystostomy generally heals quickly with a low risk of complications.

Leave a large-bore (20 or 22 French) urethral Foley catheter in place for 2 weeks.

I recommend that a 6 French double-J ureteral stent be left in place for 6 weeks. Potential benefits of the stent include:

• prevention of stricture
• stabilization and immobilization of the ureter during healing
• reduced risk of extravasation of urine
• reduced risk of angulation of the ureter
• isolation of the repair from infection, retroperitoneal fibrosis, and cancer.

I perform IVP approximately 1 week after stent removal to ensure ureteral patency.

CASE RESOLVED

Exposure is improved by widening the incision and dividing the tendonous insertions of the rectus abdominus muscles. The surgeon then removes the mass, preserving the distal ureter, which is estimated to be 12 cm in length and to have intact adventitia.

The surgeon performs a double-spatulated end-to-end ureteroureterostomy over a 6 French double-J ureteral stent that has been passed proximally into the renal pelvis and distally into the bladder. The stent is removed 6 weeks postoperatively, and an IVP the following week demonstrates excellent patency.

The author has no financial relationships relevant to this article.

CASE: Inadvertent ureteral transection

A gynecologic surgeon operates via Pfannenstiel incision to remove a 12-cm complex left adnexal mass from a 36-year-old obese woman. When she discovers that the mass is densely adherent to the pelvic peritoneum, the surgeon incises the peritoneum lateral to the mass and opens the retroperitoneal space. However, the size and relative immobility of the mass, coupled with the low transverse incision, impair visualization of retroperitoneal structures.

The surgeon clamps and divides the ovarian vessels above the mass but, afterward, suspects that the ureter has been transected and that its ends are included within the clamps. She separates the ovarian vessels above the clamp and ligates them, at which time transection of the ureter is confirmed.

How should she proceed?

The ureter is intimately associated with the female internal genitalia in a way that challenges the gynecologic surgeon to avoid it. In a small percentage of cases involving surgical extirpation in a woman who has severe pelvic pathology, ureteral injury may be inevitable.

Several variables predispose a patient to ureteral injury, including limited exposure, as in the opening case. Others include distorted anatomy of the urinary tract relative to internal genitalia and operations that require extensive resection of pelvic tissues.

This article describes:

• prevention and intraoperative recognition of ureteral injury during gynecologic surgery
• management of intraoperatively recognized ureteral injury.

Maintain a high index of suspicion

The surgeon in the opening case has already taken the first and most important step in ensuring a good outcome: She suspected ureteral injury. In high-risk situations, intraoperative recognition of ureteral injury is more likely when the operative field is inspected thoroughly during and at the conclusion of the surgical procedure.

In a high-risk case, the combined use of intravenous indigo carmine, careful inspection of the operative field, cystoscopy, and ureteral dissection is recommended and should be routine.

Common sites of injury

During gynecologic surgery, the ureter is susceptible to injury along its entire course through the pelvis (see “The ureter takes a course fraught with hazard,”).

During adnexectomy, the gonadal vessels are generally ligated 2 to 3 cm above the adnexa. The ureter lies in close proximity to these vessels and may inadvertently be included in the ligation.

During hysterectomy, the ureter is susceptible to injury as it passes through the parametrium a short distance from the uterus and vaginal fornix.

Sutures placed in the posterior lateral cul de sac during prolapse surgery lie near the midpelvic ureter, and sutures placed during vaginal cuff closure, anterior colporrhaphy, and retropubic urethropexy are in close proximity to the trigonal portion of the ureter.

The ureter takes a course fraught with hazard

The ureter extends from the renal pelvis to the bladder, with a length that ranges from 25 to 30 cm, depending on the patient’s height. It crosses the pelvic brim near the bifurcation of the common iliac artery, where it becomes the “pelvic” ureter. The abdominal and pelvic portions of the ureter are approximately equal in length.

ILLUSTRATIONS BY ROB FLEWELL FOR OBG MANAGEMENT

The blood supply of the ureter derives from branches of the major arterial system of the lower abdomen and pelvis. These branches reach the medial aspect of the abdominal ureter and the lateral side of the pelvic ureter to form an anastomotic vascular network protected by an adventitial layer surrounding the ureter.

The ureter is attached to the posterior lateral pelvic peritoneum running dorsal to ovarian vessels. At the midpelvis, it separates from the peritoneum to pierce the base of the broad ligament underneath the uterine artery. At this point, the ureter is about 1.5 to 2 cm lateral to the uterus and curves medially and ventrally, tunneling through the cardinal and vesicovaginal ligaments to enter the bladder trigone.

Risky procedures

In gynecologic surgery, ureteral injury occurs most often during abdominal hysterectomy—probably because of how frequently this operation is performed and the range of pathology managed. The incidence of ureteral injury is much higher during abdominal hysterectomy than vaginal hysterectomy.^1-4

Laparoscopic hysterectomy also has been associated with a higher incidence of ureteral injury, especially in the early phase of training.^5,6 Possible explanations include:

• greater difficulty identifying the ureter
• a steeper learning curve
• more frequent use of energy to hemostatically divide pedicles, with the potential for thermal injury
• less traction–countertraction, resulting in dissection closer to the ureter
• management of complex pathology.

Although the overall incidence of ureteral injury during adnexectomy is low, it is probably much higher in women undergoing this procedure after a previous hysterectomy or in the presence of complex adnexal pathology.

When injury is likely

Compromised exposure, distorted anatomy, and certain procedures can heighten the risk of ureteral injury. Large tumors may limit the ability of the surgeon to visualize or palpate the ureter (FIGURE 1). Extensive adhesions may cause similar difficulties, and a small incision or obesity may hinder identification of pelvic sidewall structures.

A number of pathologic conditions can distort the anatomy of the ureter, especially as it relates to the female genital tract:

• Malignancies such as ovarian cancer often encroach on and occasionally encase the ureter
• Pelvic inflammatory disease, endometriosis, and a history of surgery or pelvic radiotherapy can retract and encase the ureter toward the gynecologic tract
• Some masses expand against the lower ureter, such as cervical or broad-ligament leiomyomata or placenta previa with accreta
• During vaginal hysterectomy for complete uterine prolapse, the ureters frequently extend beyond the introitus well within the operative field
• Congenital anomalies of the ureter or hydroureter can also cause distortion.

Even in the presence of relatively normal anatomy, certain procedures predispose the ureter to injury. For example, radical hysterectomy involves the almost complete separation of the pelvic ureter from the gynecologic tract and its surrounding soft tissue. When pelvic pathology is significant, the plane of dissection will always be near the ureter.

FIGURE 1 Access to the ureter is obstructed, putting it in jeopardy

Large tumors may limit the ability of the surgeon to visualize or palpate the ureter.

Prevention is the best strategy

At least 50% of ureteral injuries reported during gynecologic surgery have occurred in the absence of a recognizable risk factor.^2,7 Nevertheless, knowledge of anatomy and the ability to recognize situations in which there is an elevated risk for ureteral injury will best enable the surgeon to prevent such injury.

When a high-risk situation is encountered, critical preventive steps include:

• adequate exposure
• competent assistance
• exposure of the path of the ureter through the planned course of dissection. Dissecting the ureter beyond this area is usually unnecessary and may itself cause injury.

Skip preoperative IVP in most cases

The vast majority of women who undergo gynecologic surgery do not benefit from preoperative intravenous pyelography (IVP). This measure does not appear to reduce the likelihood of ureteral injury, even in the face of obvious gynecologic disease. However, preoperative identification of obvious ureteral involvement by the disease process is useful. In such cases, the plane of dissection will probably lie closer to the ureter. One of the goals of surgery will then be to clear the urinary tract from the affected area.

When there is a high index of suspicion of an abnormality such as obstruction, intrinsic ureteral endometriosis, or congenital anomaly, preoperative IVP is indicated.

A stent may be helpful in some cases

Ureteral stents are sometimes placed in order to aid in identification and dissection of the ureters during surgery. Some authors of reports on this topic, including Hoffman, believe that stents are useful in certain situations, such as excision of an ovarian remnant, radical vaginal hysterectomy, and when pelvic organs are encased by malignant ovarian tumors. However, stents do not clearly reduce the risk of injury and, in some cases, may increase the risk by providing a false sense of security and predisposing the ureter to adventitial injury during difficult dissection.

Anticipate the effects of disease

The surgeon must have a thorough knowledge of the gynecologic disease process as it relates to surgery involving the urinary tract. For example, an ovarian remnant will almost always be somewhat densely adherent to the pelvic ureter. When severe endometriosis involves the posterior leaf of the broad ligament, the ureter will often be fibrotically retracted toward the operative field.

Certain procedures have special challenges. During resection of adnexa, for example, it is important that the ureter be identified in the retroperitoneum before the ovarian vessels are ligated. During hysterectomy, soft tissues that contain the bladder and ureters should be mobilized caudally and laterally, respectively, creating a U-shaped region (“U” for urinary tract, FIGURE 2) to which the surgeon must limit dissection.

FIGURE 2 During hysterectomy, mobilize the bladder and ureter

Mobilize the soft tissues that contain the bladder and ureters caudally and laterally, respectively, creating a U-shaped region. During division of the paracervical tissues, the surgeon must remain within this region.

Intraoperative detection

Two main types of ureteral injury occur during gynecologic surgery: transection and destruction. The latter includes ligation, crushing, devascularization, and thermal injury.

Intraoperative detection of ureteral injury is more likely when the surgeon recognizes at the outset that the operation places the ureter at increased risk. When dissection has been difficult or complicated for any reason, be concerned about possible injury.

In general, ureteral injury is first recognized by careful inspection of the surgical field. Begin by instilling 5 ml of indigo carmine intravenously. Once the dye begins to appear in the Foley catheter, inspect the area of dissection under a small amount of irrigation fluid, looking for extravasation of dye that indicates partial or complete transection.

If no injury is identified, cystoscopy is the next step. I perform all major abdominal operations with the patient in the low lithotomy position, which provides easy access to the perineum. Cystoscopic identification of urine jetting from both ureteral orifices confirms patency. When only wisps of dye are observed, it is likely that the ureter in question has been partially occluded (e.g., by acute angulation). Failure of any urine to appear from one of the orifices highly suggests injury to that ureter.

During inspection of the operative field, attempt to pass a ureteral stent into the affected orifice. If the stent passes easily and dyed urine is seen to drip freely from it, look for possible angulation of the ureter. If you find none, remove the stent and inspect the orifice again for jetting urine.

If the ureteral stent will move only a few centimeters into the ureteral orifice, ligation (with or without transection) is likely. In this case, leave the stent in place. If the operative site is readily accessible, dissect the applicable area to identify the problem. Depending on the circumstances, you may wish to infuse dye through the stent to aid in operative identification or radiographic evaluation.

Intraoperative IVP may be useful, especially when cystoscopy is unavailable.

Fundamentals of repair

Repair of major injury to the pelvic ureter is generally best accomplished by ureteroneocystostomy or, in selected cases involving injury to the proximal pelvic ureter, by ureteroureterostomy.

When intraoperatively recognized injury to the pelvic ureter appears to be minor, it can be managed by placing a ureteral stent and a closed-suction pelvic drain. Also consider wrapping the injured area with vascularized tissue such as perivesical fat. Minor lacerations can be closed perpendicular to the axis of the ureter using interrupted 4-0 delayed absorbable suture.

Most injuries to the pelvic ureter are optimally managed by ureteroneocystostomy (FIGURE 3). When a significant portion of the pelvic ureter has been lost, ureteroneocystostomy usually requires a combination of:

• extensive mobilization of the bladder
• conservative mobilization of the ureter
• elongation of the bladder
• psoas hitch.

When necessary, mobilization of the kidney with suturing of the caudal perinephric fascia to the psoas muscle will bridge an additional 2- to 3-cm gap.

Major injury to the distal half of the pelvic ureter is repaired using straightforward ureteroneocystostomy.

When there is no significant pelvic disease and the distal ureter is healthy, injury to the proximal pelvic ureter during division of the ovarian vessels may be repaired via ureteroureterostomy. If the ureteral ends will be anastomosed on tension or there is any question about the integrity of the distal portion of the ureter, as when extensive distal ureterolysis has been necessary, consider ureteroneocystostomy.

FIGURE 3 When the distal ureter is injured

Most injuries to the pelvic ureter are managed optimally by ureteroneocystostomy.

Postoperative management

After repair of a ureteral injury, leave a closed-suction pelvic drain in place for 2 to 3 days so that any major urinary leak can be detected; it also enhances spontaneous closure and helps prevent potentially infected fluid from accumulating in the region of anastomosis.

The cystotomy performed during ureteroneocystostomy generally heals quickly with a low risk of complications.

Leave a large-bore (20 or 22 French) urethral Foley catheter in place for 2 weeks.

I recommend that a 6 French double-J ureteral stent be left in place for 6 weeks. Potential benefits of the stent include:

• prevention of stricture
• stabilization and immobilization of the ureter during healing
• reduced risk of extravasation of urine
• reduced risk of angulation of the ureter
• isolation of the repair from infection, retroperitoneal fibrosis, and cancer.

I perform IVP approximately 1 week after stent removal to ensure ureteral patency.

CASE RESOLVED

Exposure is improved by widening the incision and dividing the tendonous insertions of the rectus abdominus muscles. The surgeon then removes the mass, preserving the distal ureter, which is estimated to be 12 cm in length and to have intact adventitia.

The surgeon performs a double-spatulated end-to-end ureteroureterostomy over a 6 French double-J ureteral stent that has been passed proximally into the renal pelvis and distally into the bladder. The stent is removed 6 weeks postoperatively, and an IVP the following week demonstrates excellent patency.