A   43-year-old woman presented to the  clinic complaining of bilateral ankle joint pain for 2 months. She denied a history of fever, weight loss, addictions, cough, or trauma. On physical examinatio, she had swelling of the ankle and wrist joints and digital clubbing (Figure 1). Active movement of the ankles and wrists was restricted due to pain. The examination was otherwise unremarkable.

Radiography of both ankles showed a lamellar type periosteal reaction suggestive of periostitis (Figure 2). Computed tomography of the chest revealed a spiculated mass over the right lower lobe. Biopsy study of the mass was positive for squamous cell carcinoma. She was referred to the oncology center for further management.

FEATURES OF HYPERTROPHIC OSTEOARTHROPATHY

Digital clubbing is one of the oldest signs in clinical medicine. It is characterized by bulbous enlargement of the terminal segments of the fingers and toes due to proliferation of subungual connective tissue. It usually appears as a painless finger deformity and is clinically appreciated as a loss of the normal angle between the nail bed and proximal nail fold.

Hypertrophic osteoarthropathy is a symptomatic form of clubbing associated with proliferative periostosis of the distal end of long tubular bones, commonly those adjacent to the wrist and ankle joints.¹ The laminated appearance of these bones on radiography is due to the excess connective tissue secondary to new osteoid material deposited under the periosteum.

There is evidence to suggest that clubbing and hypertrophic osteoarthropathy represent different stages of the same disease process.² In most cases, finger deformity is the first manifestation; as the disease progresses, periostosis becomes evident.

Hypertrophic osteoarthropathy can be classified as primary or secondary. The primary form, also known as primary pachydermoperiostosis, is rare and constitutes only 3% of all cases.³ The exact cause is not yet known; it occurs as a hereditary disease with autosomal dominant inheritance with variable penetrance. Congenital clubbing without periostosis is of no clinical significance.⁴

CONDITIONS ASSOCIATED WITH CLUBBING

Primary bronchogenic carcinoma is the most common cause of clubbing and hypertrophic osteoarthropathy. In one retrospective series, 4.5% of patients with lung cancer had radiologic evidence of hypertrophic osteoarthropathy.⁵ Other malignancies associated with this condition are mesothelioma, hepatocellular carcinoma, and certain types of gastrointestinal adenocarcinoma.

Other conditions associated with clubbing include:

• Cardiovascular disease such as congenital cyanotic heart disease and infective endocarditis
• Gastrointestinal conditions such as cirrhosis, primary sclerosing cholangitis, Crohn disease, and ulcerative colitis
• Infections such as lung abscess and empyema.

Clubbing is generally bilaterally symmetrical. Asymmetric clubbing is rare and usually indicates impaired regional blood flow due to vascular disease. Unilateral clubbing or hypertrophic osteoarthropathy restricted to 1 upper limb can result from an anomaly of the aortic arch or from a subclavian or brachial artery aneurysm. Clubbing affecting predominantly the lower limbs has been reported in coarctation of aorta and patent ductus arteriosus.⁶ Rare cases of unidigital clubbing are reported in sarcoidosis.⁷

The importance of recognizing hypertrophic osteoarthropathy cannot be overemphasized. If any of the manifestations of the syndrome become evident in a previously healthy person, a thorough evaluation for an underlying disease should be done.

Clubbing should be differentiated from pseudoclubbing, which is seen in conditions such as hyperparathyroidism and scleroderma. The central mechanism for nail deformity in pseudoclubbing is acro-osteolysis with the resulting collapse of the subungual soft tissues. The important features differentiating it from true clubbing are preservation of the angle between the nail bed and proximal nail fold and asymmetric finger involvement.⁸

MANAGEMENT

The management of primary hypertrophic osteoarthropathy focuses on relieving the symptoms of periosteitis. Secondary forms require a detailed evaluation to rule out the underlying disease. In refractory cases, a bone-modifying agent (eg, zoledronic acid),⁹ octreotide,¹⁰ nonsteroidal anti-inflammatory drugs, or vagotomy¹¹ may help.

A   43-year-old woman presented to the  clinic complaining of bilateral ankle joint pain for 2 months. She denied a history of fever, weight loss, addictions, cough, or trauma. On physical examinatio, she had swelling of the ankle and wrist joints and digital clubbing (Figure 1). Active movement of the ankles and wrists was restricted due to pain. The examination was otherwise unremarkable.

Radiography of both ankles showed a lamellar type periosteal reaction suggestive of periostitis (Figure 2). Computed tomography of the chest revealed a spiculated mass over the right lower lobe. Biopsy study of the mass was positive for squamous cell carcinoma. She was referred to the oncology center for further management.

FEATURES OF HYPERTROPHIC OSTEOARTHROPATHY

Digital clubbing is one of the oldest signs in clinical medicine. It is characterized by bulbous enlargement of the terminal segments of the fingers and toes due to proliferation of subungual connective tissue. It usually appears as a painless finger deformity and is clinically appreciated as a loss of the normal angle between the nail bed and proximal nail fold.

Hypertrophic osteoarthropathy is a symptomatic form of clubbing associated with proliferative periostosis of the distal end of long tubular bones, commonly those adjacent to the wrist and ankle joints.¹ The laminated appearance of these bones on radiography is due to the excess connective tissue secondary to new osteoid material deposited under the periosteum.

There is evidence to suggest that clubbing and hypertrophic osteoarthropathy represent different stages of the same disease process.² In most cases, finger deformity is the first manifestation; as the disease progresses, periostosis becomes evident.

Hypertrophic osteoarthropathy can be classified as primary or secondary. The primary form, also known as primary pachydermoperiostosis, is rare and constitutes only 3% of all cases.³ The exact cause is not yet known; it occurs as a hereditary disease with autosomal dominant inheritance with variable penetrance. Congenital clubbing without periostosis is of no clinical significance.⁴

CONDITIONS ASSOCIATED WITH CLUBBING

Primary bronchogenic carcinoma is the most common cause of clubbing and hypertrophic osteoarthropathy. In one retrospective series, 4.5% of patients with lung cancer had radiologic evidence of hypertrophic osteoarthropathy.⁵ Other malignancies associated with this condition are mesothelioma, hepatocellular carcinoma, and certain types of gastrointestinal adenocarcinoma.

Other conditions associated with clubbing include:

• Cardiovascular disease such as congenital cyanotic heart disease and infective endocarditis
• Gastrointestinal conditions such as cirrhosis, primary sclerosing cholangitis, Crohn disease, and ulcerative colitis
• Infections such as lung abscess and empyema.

Clubbing is generally bilaterally symmetrical. Asymmetric clubbing is rare and usually indicates impaired regional blood flow due to vascular disease. Unilateral clubbing or hypertrophic osteoarthropathy restricted to 1 upper limb can result from an anomaly of the aortic arch or from a subclavian or brachial artery aneurysm. Clubbing affecting predominantly the lower limbs has been reported in coarctation of aorta and patent ductus arteriosus.⁶ Rare cases of unidigital clubbing are reported in sarcoidosis.⁷

The importance of recognizing hypertrophic osteoarthropathy cannot be overemphasized. If any of the manifestations of the syndrome become evident in a previously healthy person, a thorough evaluation for an underlying disease should be done.

Clubbing should be differentiated from pseudoclubbing, which is seen in conditions such as hyperparathyroidism and scleroderma. The central mechanism for nail deformity in pseudoclubbing is acro-osteolysis with the resulting collapse of the subungual soft tissues. The important features differentiating it from true clubbing are preservation of the angle between the nail bed and proximal nail fold and asymmetric finger involvement.⁸

MANAGEMENT

The management of primary hypertrophic osteoarthropathy focuses on relieving the symptoms of periosteitis. Secondary forms require a detailed evaluation to rule out the underlying disease. In refractory cases, a bone-modifying agent (eg, zoledronic acid),⁹ octreotide,¹⁰ nonsteroidal anti-inflammatory drugs, or vagotomy¹¹ may help.

A   43-year-old woman presented to the  clinic complaining of bilateral ankle joint pain for 2 months. She denied a history of fever, weight loss, addictions, cough, or trauma. On physical examinatio, she had swelling of the ankle and wrist joints and digital clubbing (Figure 1). Active movement of the ankles and wrists was restricted due to pain. The examination was otherwise unremarkable.

Radiography of both ankles showed a lamellar type periosteal reaction suggestive of periostitis (Figure 2). Computed tomography of the chest revealed a spiculated mass over the right lower lobe. Biopsy study of the mass was positive for squamous cell carcinoma. She was referred to the oncology center for further management.

FEATURES OF HYPERTROPHIC OSTEOARTHROPATHY

Digital clubbing is one of the oldest signs in clinical medicine. It is characterized by bulbous enlargement of the terminal segments of the fingers and toes due to proliferation of subungual connective tissue. It usually appears as a painless finger deformity and is clinically appreciated as a loss of the normal angle between the nail bed and proximal nail fold.

Hypertrophic osteoarthropathy is a symptomatic form of clubbing associated with proliferative periostosis of the distal end of long tubular bones, commonly those adjacent to the wrist and ankle joints.¹ The laminated appearance of these bones on radiography is due to the excess connective tissue secondary to new osteoid material deposited under the periosteum.

There is evidence to suggest that clubbing and hypertrophic osteoarthropathy represent different stages of the same disease process.² In most cases, finger deformity is the first manifestation; as the disease progresses, periostosis becomes evident.

Hypertrophic osteoarthropathy can be classified as primary or secondary. The primary form, also known as primary pachydermoperiostosis, is rare and constitutes only 3% of all cases.³ The exact cause is not yet known; it occurs as a hereditary disease with autosomal dominant inheritance with variable penetrance. Congenital clubbing without periostosis is of no clinical significance.⁴

CONDITIONS ASSOCIATED WITH CLUBBING

Primary bronchogenic carcinoma is the most common cause of clubbing and hypertrophic osteoarthropathy. In one retrospective series, 4.5% of patients with lung cancer had radiologic evidence of hypertrophic osteoarthropathy.⁵ Other malignancies associated with this condition are mesothelioma, hepatocellular carcinoma, and certain types of gastrointestinal adenocarcinoma.

Other conditions associated with clubbing include:

• Cardiovascular disease such as congenital cyanotic heart disease and infective endocarditis
• Gastrointestinal conditions such as cirrhosis, primary sclerosing cholangitis, Crohn disease, and ulcerative colitis
• Infections such as lung abscess and empyema.

Clubbing is generally bilaterally symmetrical. Asymmetric clubbing is rare and usually indicates impaired regional blood flow due to vascular disease. Unilateral clubbing or hypertrophic osteoarthropathy restricted to 1 upper limb can result from an anomaly of the aortic arch or from a subclavian or brachial artery aneurysm. Clubbing affecting predominantly the lower limbs has been reported in coarctation of aorta and patent ductus arteriosus.⁶ Rare cases of unidigital clubbing are reported in sarcoidosis.⁷

The importance of recognizing hypertrophic osteoarthropathy cannot be overemphasized. If any of the manifestations of the syndrome become evident in a previously healthy person, a thorough evaluation for an underlying disease should be done.

Clubbing should be differentiated from pseudoclubbing, which is seen in conditions such as hyperparathyroidism and scleroderma. The central mechanism for nail deformity in pseudoclubbing is acro-osteolysis with the resulting collapse of the subungual soft tissues. The important features differentiating it from true clubbing are preservation of the angle between the nail bed and proximal nail fold and asymmetric finger involvement.⁸

MANAGEMENT

The management of primary hypertrophic osteoarthropathy focuses on relieving the symptoms of periosteitis. Secondary forms require a detailed evaluation to rule out the underlying disease. In refractory cases, a bone-modifying agent (eg, zoledronic acid),⁹ octreotide,¹⁰ nonsteroidal anti-inflammatory drugs, or vagotomy¹¹ may help.

We thank those who reviewed manuscripts submitted to the Cleveland Clinic Journal of Medicine in the year ending December 31, 2016. Reviewing papers for scientific journals is an arduous task and involves considerable time and effort. We are grateful to these reviewers for contributing their expertise this past year.

—Brian F. Mandell, MD, PhD, Editor in Chief

We thank those who reviewed manuscripts submitted to the Cleveland Clinic Journal of Medicine in the year ending December 31, 2016. Reviewing papers for scientific journals is an arduous task and involves considerable time and effort. We are grateful to these reviewers for contributing their expertise this past year.

—Brian F. Mandell, MD, PhD, Editor in Chief

We thank those who reviewed manuscripts submitted to the Cleveland Clinic Journal of Medicine in the year ending December 31, 2016. Reviewing papers for scientific journals is an arduous task and involves considerable time and effort. We are grateful to these reviewers for contributing their expertise this past year.

—Brian F. Mandell, MD, PhD, Editor in Chief

Cervical dysplasia is a condition commonly encountered by the gynecologist. It is either treated (with excision or ablation) or monitored, depending on the lesion grade, cytologic history, medical history, and reproductive goals. Cervical dysplasia commonly arises in women of reproductive age. Therefore, consider reproductive effects when deciding whether to treat or monitor, as well as when choosing the treatment modality.

Background

Approximately two-thirds of human papillomavirus infections resolve within a year, and more than 90% resolve within 2 years. Similarly, low-grade cervical intraepithelial neoplasia (CIN 1) lesions frequently resolve. High-grade (CIN 2 and CIN 3) lesions regress less commonly, with 5% and 12%-40% progressing to invasive cancer, respectively. Therefore, treatment is typically recommended.

Obstetric implications

Potential obstetric risks of treatment for CIN include infertility, spontaneous abortion, preterm premature rupture of membranes (PPROM), preterm delivery, and perinatal/neonatal mortality. These risks are discussed individually below. Mechanisms that have been suggested for such complications include decreased cervical mucous, cervical scarring impeding conception or dilation, loss of cervical volume, collagen breakdown, and immunologic processes due to decreased physical defenses or microbiome shifts.

Fertility

Studies have shown that treatment does not appear to impede conception. The overall pregnancy rate is higher among treated women than untreated women. Pregnancy rates are not different among women intending to conceive or among women attempting conception for more than 12 months, with the caveat being that these studies are heterogenous.^2,3

Miscarriage

No difference has been observed in total (less than 24 weeks) miscarriage rate or first trimester (less than 12 weeks) miscarriage rate among treated and untreated women. However, the second trimester miscarriage rate is significantly higher among treated women (risk ratio, 2.60).² This risk is most notable following laser conization or LEEP.⁴ There may also be an association between ablation and pregnancy loss.

Preterm birth and PPROM

Several studies and meta-analyses show an association between preterm birth and treatment for CIN using LEEP or CKC. There is an increased risk of severe preterm delivery (relative risk, 2.78), extreme preterm delivery (relative risk, 5.33), and low birth weight (relative risk, 2.86) with CKC.⁵ LEEP is associated with the same outcomes, albeit the risk is lower than with CKC.⁶ The risk of preterm birth is even lower for ablation.⁷

Other complications

Ectopic pregnancy and termination rates may be higher in treated women, compared with untreated women.² However, there does not appear to be an increased risk for perinatal/neonatal mortality, cesarean section, or neonatal intensive care unit admission among women treated with excisional procedures.⁶

Pointers for practice

• Due to the potential for adverse obstetric complications following excisional procedures for cervical dysplasia, gynecologists should closely adhere to the American Society for Colposcopy and Cervical Pathology guidelines when determining the appropriateness of dysplasia interventions. The decision to treat, versus monitor, dysplasia in a woman who plans future childbearing should be made with the patient after thorough discussion of the risks and benefits of each path.
• Women younger than age 30 years should not be screened for high-risk human papillomavirus because of both its high incidence and its high rate of spontaneous resolution.
• For reproductive-aged women with CIN 2 and adequate colposcopy, the American Society for Colposcopy and Cervical Pathology supports either monitoring with cytology and colposcopy every 6 months for a year or excisional treatment. However, women with CIN 3, inadequate colposcopy, prior cervical cancer, diethylstilbestrol exposure, or decreased immunity should undergo excisional treatment.
• When selecting an excisional method (LEEP or CKC), surgeons should choose the most appropriate technique for the patient’s pathology but should acknowledge the observed higher rates of PPROM, preterm birth, and low-birth-weight infants among those receiving CKC, and tailor the size of the excision to the specific lesion.
• Consider recommending a 12-month interval between treatment and pregnancy to ensure resolution of high-grade dysplasia. Furthermore, obstetric risk may be increased within 12 months following treatment.

Dr. Robbins is a resident in the department of obstetrics and gynecology at the University of North Carolina, Chapel Hill. Dr. Rossi is an assistant professor in the division of gynecologic oncology at UNC, Chapel Hill. They reported having no relevant financial disclosures.

References

1. Am J Obstet Gynecol. 2011 Jul;205(1):19-27.

2. Cochrane Database Syst Rev. 2015 Sep 29;(9):CD008478.

3. BMJ. 2014 Oct 28;349:g6192.

4. Obstet Gynecol. 2016 Dec;128(6):1265-73.

5. BMJ. 2008 Sep 18;337:a1284.

6. Arch Gynecol Obstet. 2014 Jan;289(1):85-99.

7. BJOG. 2011 Aug;118(9):1031-41.

8. Obstet Gynecol. 2013 May;121(5):1063-8.

9. Lancet. 2006 Feb 11;367(9509):489-98.

10. Gynecol Obstet Invest. 2014;77(4):240-4.

Cervical dysplasia is a condition commonly encountered by the gynecologist. It is either treated (with excision or ablation) or monitored, depending on the lesion grade, cytologic history, medical history, and reproductive goals. Cervical dysplasia commonly arises in women of reproductive age. Therefore, consider reproductive effects when deciding whether to treat or monitor, as well as when choosing the treatment modality.

Background

Approximately two-thirds of human papillomavirus infections resolve within a year, and more than 90% resolve within 2 years. Similarly, low-grade cervical intraepithelial neoplasia (CIN 1) lesions frequently resolve. High-grade (CIN 2 and CIN 3) lesions regress less commonly, with 5% and 12%-40% progressing to invasive cancer, respectively. Therefore, treatment is typically recommended.

Obstetric implications

Potential obstetric risks of treatment for CIN include infertility, spontaneous abortion, preterm premature rupture of membranes (PPROM), preterm delivery, and perinatal/neonatal mortality. These risks are discussed individually below. Mechanisms that have been suggested for such complications include decreased cervical mucous, cervical scarring impeding conception or dilation, loss of cervical volume, collagen breakdown, and immunologic processes due to decreased physical defenses or microbiome shifts.

Fertility

Studies have shown that treatment does not appear to impede conception. The overall pregnancy rate is higher among treated women than untreated women. Pregnancy rates are not different among women intending to conceive or among women attempting conception for more than 12 months, with the caveat being that these studies are heterogenous.^2,3

Miscarriage

No difference has been observed in total (less than 24 weeks) miscarriage rate or first trimester (less than 12 weeks) miscarriage rate among treated and untreated women. However, the second trimester miscarriage rate is significantly higher among treated women (risk ratio, 2.60).² This risk is most notable following laser conization or LEEP.⁴ There may also be an association between ablation and pregnancy loss.

Preterm birth and PPROM

Several studies and meta-analyses show an association between preterm birth and treatment for CIN using LEEP or CKC. There is an increased risk of severe preterm delivery (relative risk, 2.78), extreme preterm delivery (relative risk, 5.33), and low birth weight (relative risk, 2.86) with CKC.⁵ LEEP is associated with the same outcomes, albeit the risk is lower than with CKC.⁶ The risk of preterm birth is even lower for ablation.⁷

Other complications

Ectopic pregnancy and termination rates may be higher in treated women, compared with untreated women.² However, there does not appear to be an increased risk for perinatal/neonatal mortality, cesarean section, or neonatal intensive care unit admission among women treated with excisional procedures.⁶

Pointers for practice

• Due to the potential for adverse obstetric complications following excisional procedures for cervical dysplasia, gynecologists should closely adhere to the American Society for Colposcopy and Cervical Pathology guidelines when determining the appropriateness of dysplasia interventions. The decision to treat, versus monitor, dysplasia in a woman who plans future childbearing should be made with the patient after thorough discussion of the risks and benefits of each path.
• Women younger than age 30 years should not be screened for high-risk human papillomavirus because of both its high incidence and its high rate of spontaneous resolution.
• For reproductive-aged women with CIN 2 and adequate colposcopy, the American Society for Colposcopy and Cervical Pathology supports either monitoring with cytology and colposcopy every 6 months for a year or excisional treatment. However, women with CIN 3, inadequate colposcopy, prior cervical cancer, diethylstilbestrol exposure, or decreased immunity should undergo excisional treatment.
• When selecting an excisional method (LEEP or CKC), surgeons should choose the most appropriate technique for the patient’s pathology but should acknowledge the observed higher rates of PPROM, preterm birth, and low-birth-weight infants among those receiving CKC, and tailor the size of the excision to the specific lesion.
• Consider recommending a 12-month interval between treatment and pregnancy to ensure resolution of high-grade dysplasia. Furthermore, obstetric risk may be increased within 12 months following treatment.

Dr. Robbins is a resident in the department of obstetrics and gynecology at the University of North Carolina, Chapel Hill. Dr. Rossi is an assistant professor in the division of gynecologic oncology at UNC, Chapel Hill. They reported having no relevant financial disclosures.

References

1. Am J Obstet Gynecol. 2011 Jul;205(1):19-27.

2. Cochrane Database Syst Rev. 2015 Sep 29;(9):CD008478.

3. BMJ. 2014 Oct 28;349:g6192.

4. Obstet Gynecol. 2016 Dec;128(6):1265-73.

5. BMJ. 2008 Sep 18;337:a1284.

6. Arch Gynecol Obstet. 2014 Jan;289(1):85-99.

7. BJOG. 2011 Aug;118(9):1031-41.

8. Obstet Gynecol. 2013 May;121(5):1063-8.

9. Lancet. 2006 Feb 11;367(9509):489-98.

10. Gynecol Obstet Invest. 2014;77(4):240-4.

Cervical dysplasia is a condition commonly encountered by the gynecologist. It is either treated (with excision or ablation) or monitored, depending on the lesion grade, cytologic history, medical history, and reproductive goals. Cervical dysplasia commonly arises in women of reproductive age. Therefore, consider reproductive effects when deciding whether to treat or monitor, as well as when choosing the treatment modality.

Background

Approximately two-thirds of human papillomavirus infections resolve within a year, and more than 90% resolve within 2 years. Similarly, low-grade cervical intraepithelial neoplasia (CIN 1) lesions frequently resolve. High-grade (CIN 2 and CIN 3) lesions regress less commonly, with 5% and 12%-40% progressing to invasive cancer, respectively. Therefore, treatment is typically recommended.

Obstetric implications

Potential obstetric risks of treatment for CIN include infertility, spontaneous abortion, preterm premature rupture of membranes (PPROM), preterm delivery, and perinatal/neonatal mortality. These risks are discussed individually below. Mechanisms that have been suggested for such complications include decreased cervical mucous, cervical scarring impeding conception or dilation, loss of cervical volume, collagen breakdown, and immunologic processes due to decreased physical defenses or microbiome shifts.

Fertility

Studies have shown that treatment does not appear to impede conception. The overall pregnancy rate is higher among treated women than untreated women. Pregnancy rates are not different among women intending to conceive or among women attempting conception for more than 12 months, with the caveat being that these studies are heterogenous.^2,3

Miscarriage

No difference has been observed in total (less than 24 weeks) miscarriage rate or first trimester (less than 12 weeks) miscarriage rate among treated and untreated women. However, the second trimester miscarriage rate is significantly higher among treated women (risk ratio, 2.60).² This risk is most notable following laser conization or LEEP.⁴ There may also be an association between ablation and pregnancy loss.

Preterm birth and PPROM

Several studies and meta-analyses show an association between preterm birth and treatment for CIN using LEEP or CKC. There is an increased risk of severe preterm delivery (relative risk, 2.78), extreme preterm delivery (relative risk, 5.33), and low birth weight (relative risk, 2.86) with CKC.⁵ LEEP is associated with the same outcomes, albeit the risk is lower than with CKC.⁶ The risk of preterm birth is even lower for ablation.⁷

Other complications

Ectopic pregnancy and termination rates may be higher in treated women, compared with untreated women.² However, there does not appear to be an increased risk for perinatal/neonatal mortality, cesarean section, or neonatal intensive care unit admission among women treated with excisional procedures.⁶

Pointers for practice

• Due to the potential for adverse obstetric complications following excisional procedures for cervical dysplasia, gynecologists should closely adhere to the American Society for Colposcopy and Cervical Pathology guidelines when determining the appropriateness of dysplasia interventions. The decision to treat, versus monitor, dysplasia in a woman who plans future childbearing should be made with the patient after thorough discussion of the risks and benefits of each path.
• Women younger than age 30 years should not be screened for high-risk human papillomavirus because of both its high incidence and its high rate of spontaneous resolution.
• For reproductive-aged women with CIN 2 and adequate colposcopy, the American Society for Colposcopy and Cervical Pathology supports either monitoring with cytology and colposcopy every 6 months for a year or excisional treatment. However, women with CIN 3, inadequate colposcopy, prior cervical cancer, diethylstilbestrol exposure, or decreased immunity should undergo excisional treatment.
• When selecting an excisional method (LEEP or CKC), surgeons should choose the most appropriate technique for the patient’s pathology but should acknowledge the observed higher rates of PPROM, preterm birth, and low-birth-weight infants among those receiving CKC, and tailor the size of the excision to the specific lesion.
• Consider recommending a 12-month interval between treatment and pregnancy to ensure resolution of high-grade dysplasia. Furthermore, obstetric risk may be increased within 12 months following treatment.

Dr. Robbins is a resident in the department of obstetrics and gynecology at the University of North Carolina, Chapel Hill. Dr. Rossi is an assistant professor in the division of gynecologic oncology at UNC, Chapel Hill. They reported having no relevant financial disclosures.

References

1. Am J Obstet Gynecol. 2011 Jul;205(1):19-27.

2. Cochrane Database Syst Rev. 2015 Sep 29;(9):CD008478.

3. BMJ. 2014 Oct 28;349:g6192.

4. Obstet Gynecol. 2016 Dec;128(6):1265-73.

5. BMJ. 2008 Sep 18;337:a1284.

6. Arch Gynecol Obstet. 2014 Jan;289(1):85-99.

7. BJOG. 2011 Aug;118(9):1031-41.

8. Obstet Gynecol. 2013 May;121(5):1063-8.

9. Lancet. 2006 Feb 11;367(9509):489-98.

10. Gynecol Obstet Invest. 2014;77(4):240-4.

Electronic fetal monitoring (EFM) is the most commonly used instrument in obstetrics and is the perceived standard of care. However, the U.S. Preventive Services Task Force recommended against its use in low-risk women in 1996 (a “D” rating) – signifying the lack of evidence for benefit and the potential for harm – and said there was insufficient evidence to recommend for or against its use in high-risk women (a “C” rating).

Today, available data still suggest that EFM does not reduce overall perinatal mortality or the risk of cerebral palsy. Moreover, its use is associated with increased operative vaginal deliveries and cesarean deliveries.

Emerging research

An abnormal or indeterminate fetal heart rate tracing is the second most common indication for primary cesarean, after labor arrest, according to a study published in 2011 of more than 32,000 live births. Given the rarity of category III tracings (“abnormal”), it is likely that category II tracings (“indeterminate”) account for most of the cesarean deliveries performed out of concern for fetal acidemia (Obstet Gynecol. 2011 Jul;118[1]:29-38).

Until recently, we’ve known very little about the patterns contained within category II of our current three-tier system for categorizing fetal heart rate patterns. The system was defined by the 2008 consensus workshop sponsored by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the American College of Obstetricians and Gynecologists, and the Society for Maternal-Fetal Medicine (Obstet Gynecol. 2008 Sep;112[3]:661-6).

We have reasonable data to know that the vast majority of patients with category I fetal heart rate tracings will have a normal pH. We also have reasonable data showing us that patients with category III tracings have a high risk of acidemia and morbidity. However, the majority of tracings we see during labor at term fall into category II, with no clear indication of risk and characterized most often by the presence of decelerations.

As we’ve delved more deeply into the highly variable and complex category II tracings defined in 2008, we’ve begun to demonstrate that tracings can have different meanings for different patients, and that particular clinical factors can make EFM patterns more informative and predictive. In other words, EFM patterns may require different interpretations based on a priori risk and clinical factors.

One of these factors may be the presence of meconium. In a prospective cohort of more than 3,000 women with category II tracings, the presence of meconium – especially thick meconium – was associated with a higher risk of acidemia and neonatal morbidity than when meconium was absent. Interestingly, the negative predictive value was higher than the overall predictive ability in this cohort, which suggests that the absence of meconium in the setting of a category II tracing can be considered a reassuring feature (Am J Obstet Gynecol. 2014;211:644.e1-8).

We have also found through retrospective cohort studies that magnesium sulfate can impact fetal heart rate tracings, causing a transient decrease in variability (Obstet Gynecol. 2012 Jun;119[6]:1129-36 and Am J Perinatol. 2014 Nov;31[10]:869-74). In addition, intrauterine growth restricted fetuses have a higher risk of decelerations without a commensurate higher risk of morbidity (Am J Perinatol. 2015 Jul;32[9]:873-8).

Such findings need to be reproduced, expanded, and further analyzed to show us how the risk of acidemia can be better predicted. For now, just as we increasingly appreciate that tracings have a transient nature and should be considered with two lenses – one looking back in time and one looking forward – we have a growing sense that EFM should not be interpreted without consideration of clinical factors.

Research at our institution and others has shown that acidemia is more significantly associated with non-NICHD measures of fetal heart rate deceleration than with each of the main deceleration types defined by the 2008 NICHD system (i.e., repetitive variable, repetitive late, and repetitive prolonged).

For instance, Emily Hamilton, MD, and her colleagues at PeriGen, a perinatal software company, found that only prolonged decelerations, in addition to the variability within the deceleration and a depth below 60 beats per minute for more than 60 seconds, could discriminate between cases of metabolic acidosis and those with normal umbilical artery gases (J Matern Fetal Neonatal Med. 2012 Jun;25[6]:648-53).

In a 4-year retrospective cohort study of nearly 5,340 consecutive singleton, term, nonanomalous gestations, we found acidemia was most significantly associated with a calculation of the “total deceleration area” – the sum of the estimates of area within all the decelerations. This measure accounted for the frequency, depth, and duration of all decelerations in the final 30 minutes of EFM.

Each of the NICHD deceleration types was associated in our study with acidemia after adjustment for fever, obesity, prolonged first stage, and nulliparity. However, total deceleration area had superior predictive ability. After the same adjustments were made, an abnormal total deceleration area (greater than the 95th percentile) was significantly associated with an increased risk for acidemia (odds ratio, 3.79) (Am J Obstet Gynecol. 2012 Sep;207[3]:206.e1-8).

Pathophysiologically, it seems logical that the total area is most predictive, as it captures both the temporal and dose effect of decelerations. At this point, however, we can only apply this concept crudely at the bedside. There is more work to do to translate such findings into software-driven bedside tools.

Gaining reassurance

Although efforts to manage intrapartum fetal heart rate tracings focus largely on attempting to better predict who is at greatest risk for acidemia, it is important and worthwhile that we also attempt to determine whether a fetus with a category II tracing is not acidotic.

Research has consistently shown that the presence of accelerations, whether spontaneous or stimulated, is a highly reliable indicator of normal neonatal umbilical cord pH. It is therefore reasonable, when faced with indeterminate tracings (e.g., minimal variability), to consider scalp stimulation to elicit fetal heart rate acceleration. Scalp stimulation is the easiest noninvasive tool to employ to quickly secure clinical reassurance – within a couple of minutes – that the fetus is not acidotic.

For guidance on managing repetitive variable decelerations, amnioinfusion with normal saline is similarly worthy of consideration. It has been demonstrated (Level A evidence) to resolve variable fetal heart rate decelerations and reduce the incidence of cesarean delivery for nonreassuring fetal heart rate patterns. Both amnioinfusion and scalp stimulation are recommended in the 2014 ACOG/SMFM consensus statement on “Safe Prevention of the Primary Cesarean Delivery” (Obstet Gynecol. 2014 Mar;123[3]:693-711).

Oxygen administration, on the other hand, is ingrained in practice and is included in the American College of Obstetricians and Gynecologists’ practice bulletin on managing intrapartum fetal rate tracings. It is listed as a possible resuscitative measure for category II or III tracings, despite the fact that there are extremely limited data for its effectiveness or safety in labor.

Maureen S. Hamel, MD, and her colleagues at the Warren Albert Medical School at Brown University reviewed the literature and concluded that the only two randomized trials investigating the use of maternal oxygen supplementation in laboring women do not support the idea that supplementation may benefit the fetus. Moreover, they contended that oxygen supplementation may even be harmful (Am J Obstet Gynecol. 2014 Aug;211[2]:124-7).

If supplemental oxygen were a medication, we would want to know the dose, as well as the length and duration of administration before fetal heart rate tracing improved. We don’t know the answers to these questions.

There is research ongoing, both observational studies and at least one registered randomized clinical trial, that should provide more information and guidance on the impact of supplemental oxygen in the setting of category II fetal heart rate patterns. I do not expect these findings to resolve all the questions. We’re going to need a thorough body of work to provide us with definitive answers.
 

Dr. Cahill is the chief of the division of maternal-fetal medicine at Washington University in St. Louis. She reported having no financial disclosures relevant to this Master Class.

Electronic fetal monitoring (EFM) is the most commonly used instrument in obstetrics and is the perceived standard of care. However, the U.S. Preventive Services Task Force recommended against its use in low-risk women in 1996 (a “D” rating) – signifying the lack of evidence for benefit and the potential for harm – and said there was insufficient evidence to recommend for or against its use in high-risk women (a “C” rating).

Today, available data still suggest that EFM does not reduce overall perinatal mortality or the risk of cerebral palsy. Moreover, its use is associated with increased operative vaginal deliveries and cesarean deliveries.

Emerging research

An abnormal or indeterminate fetal heart rate tracing is the second most common indication for primary cesarean, after labor arrest, according to a study published in 2011 of more than 32,000 live births. Given the rarity of category III tracings (“abnormal”), it is likely that category II tracings (“indeterminate”) account for most of the cesarean deliveries performed out of concern for fetal acidemia (Obstet Gynecol. 2011 Jul;118[1]:29-38).

Until recently, we’ve known very little about the patterns contained within category II of our current three-tier system for categorizing fetal heart rate patterns. The system was defined by the 2008 consensus workshop sponsored by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the American College of Obstetricians and Gynecologists, and the Society for Maternal-Fetal Medicine (Obstet Gynecol. 2008 Sep;112[3]:661-6).

We have reasonable data to know that the vast majority of patients with category I fetal heart rate tracings will have a normal pH. We also have reasonable data showing us that patients with category III tracings have a high risk of acidemia and morbidity. However, the majority of tracings we see during labor at term fall into category II, with no clear indication of risk and characterized most often by the presence of decelerations.

As we’ve delved more deeply into the highly variable and complex category II tracings defined in 2008, we’ve begun to demonstrate that tracings can have different meanings for different patients, and that particular clinical factors can make EFM patterns more informative and predictive. In other words, EFM patterns may require different interpretations based on a priori risk and clinical factors.

One of these factors may be the presence of meconium. In a prospective cohort of more than 3,000 women with category II tracings, the presence of meconium – especially thick meconium – was associated with a higher risk of acidemia and neonatal morbidity than when meconium was absent. Interestingly, the negative predictive value was higher than the overall predictive ability in this cohort, which suggests that the absence of meconium in the setting of a category II tracing can be considered a reassuring feature (Am J Obstet Gynecol. 2014;211:644.e1-8).

We have also found through retrospective cohort studies that magnesium sulfate can impact fetal heart rate tracings, causing a transient decrease in variability (Obstet Gynecol. 2012 Jun;119[6]:1129-36 and Am J Perinatol. 2014 Nov;31[10]:869-74). In addition, intrauterine growth restricted fetuses have a higher risk of decelerations without a commensurate higher risk of morbidity (Am J Perinatol. 2015 Jul;32[9]:873-8).

Such findings need to be reproduced, expanded, and further analyzed to show us how the risk of acidemia can be better predicted. For now, just as we increasingly appreciate that tracings have a transient nature and should be considered with two lenses – one looking back in time and one looking forward – we have a growing sense that EFM should not be interpreted without consideration of clinical factors.

Research at our institution and others has shown that acidemia is more significantly associated with non-NICHD measures of fetal heart rate deceleration than with each of the main deceleration types defined by the 2008 NICHD system (i.e., repetitive variable, repetitive late, and repetitive prolonged).

For instance, Emily Hamilton, MD, and her colleagues at PeriGen, a perinatal software company, found that only prolonged decelerations, in addition to the variability within the deceleration and a depth below 60 beats per minute for more than 60 seconds, could discriminate between cases of metabolic acidosis and those with normal umbilical artery gases (J Matern Fetal Neonatal Med. 2012 Jun;25[6]:648-53).

In a 4-year retrospective cohort study of nearly 5,340 consecutive singleton, term, nonanomalous gestations, we found acidemia was most significantly associated with a calculation of the “total deceleration area” – the sum of the estimates of area within all the decelerations. This measure accounted for the frequency, depth, and duration of all decelerations in the final 30 minutes of EFM.

Each of the NICHD deceleration types was associated in our study with acidemia after adjustment for fever, obesity, prolonged first stage, and nulliparity. However, total deceleration area had superior predictive ability. After the same adjustments were made, an abnormal total deceleration area (greater than the 95th percentile) was significantly associated with an increased risk for acidemia (odds ratio, 3.79) (Am J Obstet Gynecol. 2012 Sep;207[3]:206.e1-8).

Pathophysiologically, it seems logical that the total area is most predictive, as it captures both the temporal and dose effect of decelerations. At this point, however, we can only apply this concept crudely at the bedside. There is more work to do to translate such findings into software-driven bedside tools.

Gaining reassurance

Although efforts to manage intrapartum fetal heart rate tracings focus largely on attempting to better predict who is at greatest risk for acidemia, it is important and worthwhile that we also attempt to determine whether a fetus with a category II tracing is not acidotic.

Research has consistently shown that the presence of accelerations, whether spontaneous or stimulated, is a highly reliable indicator of normal neonatal umbilical cord pH. It is therefore reasonable, when faced with indeterminate tracings (e.g., minimal variability), to consider scalp stimulation to elicit fetal heart rate acceleration. Scalp stimulation is the easiest noninvasive tool to employ to quickly secure clinical reassurance – within a couple of minutes – that the fetus is not acidotic.

For guidance on managing repetitive variable decelerations, amnioinfusion with normal saline is similarly worthy of consideration. It has been demonstrated (Level A evidence) to resolve variable fetal heart rate decelerations and reduce the incidence of cesarean delivery for nonreassuring fetal heart rate patterns. Both amnioinfusion and scalp stimulation are recommended in the 2014 ACOG/SMFM consensus statement on “Safe Prevention of the Primary Cesarean Delivery” (Obstet Gynecol. 2014 Mar;123[3]:693-711).

Oxygen administration, on the other hand, is ingrained in practice and is included in the American College of Obstetricians and Gynecologists’ practice bulletin on managing intrapartum fetal rate tracings. It is listed as a possible resuscitative measure for category II or III tracings, despite the fact that there are extremely limited data for its effectiveness or safety in labor.

Maureen S. Hamel, MD, and her colleagues at the Warren Albert Medical School at Brown University reviewed the literature and concluded that the only two randomized trials investigating the use of maternal oxygen supplementation in laboring women do not support the idea that supplementation may benefit the fetus. Moreover, they contended that oxygen supplementation may even be harmful (Am J Obstet Gynecol. 2014 Aug;211[2]:124-7).

If supplemental oxygen were a medication, we would want to know the dose, as well as the length and duration of administration before fetal heart rate tracing improved. We don’t know the answers to these questions.

There is research ongoing, both observational studies and at least one registered randomized clinical trial, that should provide more information and guidance on the impact of supplemental oxygen in the setting of category II fetal heart rate patterns. I do not expect these findings to resolve all the questions. We’re going to need a thorough body of work to provide us with definitive answers.
 

Dr. Cahill is the chief of the division of maternal-fetal medicine at Washington University in St. Louis. She reported having no financial disclosures relevant to this Master Class.

Electronic fetal monitoring (EFM) is the most commonly used instrument in obstetrics and is the perceived standard of care. However, the U.S. Preventive Services Task Force recommended against its use in low-risk women in 1996 (a “D” rating) – signifying the lack of evidence for benefit and the potential for harm – and said there was insufficient evidence to recommend for or against its use in high-risk women (a “C” rating).

Today, available data still suggest that EFM does not reduce overall perinatal mortality or the risk of cerebral palsy. Moreover, its use is associated with increased operative vaginal deliveries and cesarean deliveries.

Emerging research

An abnormal or indeterminate fetal heart rate tracing is the second most common indication for primary cesarean, after labor arrest, according to a study published in 2011 of more than 32,000 live births. Given the rarity of category III tracings (“abnormal”), it is likely that category II tracings (“indeterminate”) account for most of the cesarean deliveries performed out of concern for fetal acidemia (Obstet Gynecol. 2011 Jul;118[1]:29-38).

Until recently, we’ve known very little about the patterns contained within category II of our current three-tier system for categorizing fetal heart rate patterns. The system was defined by the 2008 consensus workshop sponsored by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the American College of Obstetricians and Gynecologists, and the Society for Maternal-Fetal Medicine (Obstet Gynecol. 2008 Sep;112[3]:661-6).

We have reasonable data to know that the vast majority of patients with category I fetal heart rate tracings will have a normal pH. We also have reasonable data showing us that patients with category III tracings have a high risk of acidemia and morbidity. However, the majority of tracings we see during labor at term fall into category II, with no clear indication of risk and characterized most often by the presence of decelerations.

As we’ve delved more deeply into the highly variable and complex category II tracings defined in 2008, we’ve begun to demonstrate that tracings can have different meanings for different patients, and that particular clinical factors can make EFM patterns more informative and predictive. In other words, EFM patterns may require different interpretations based on a priori risk and clinical factors.

One of these factors may be the presence of meconium. In a prospective cohort of more than 3,000 women with category II tracings, the presence of meconium – especially thick meconium – was associated with a higher risk of acidemia and neonatal morbidity than when meconium was absent. Interestingly, the negative predictive value was higher than the overall predictive ability in this cohort, which suggests that the absence of meconium in the setting of a category II tracing can be considered a reassuring feature (Am J Obstet Gynecol. 2014;211:644.e1-8).

We have also found through retrospective cohort studies that magnesium sulfate can impact fetal heart rate tracings, causing a transient decrease in variability (Obstet Gynecol. 2012 Jun;119[6]:1129-36 and Am J Perinatol. 2014 Nov;31[10]:869-74). In addition, intrauterine growth restricted fetuses have a higher risk of decelerations without a commensurate higher risk of morbidity (Am J Perinatol. 2015 Jul;32[9]:873-8).

Such findings need to be reproduced, expanded, and further analyzed to show us how the risk of acidemia can be better predicted. For now, just as we increasingly appreciate that tracings have a transient nature and should be considered with two lenses – one looking back in time and one looking forward – we have a growing sense that EFM should not be interpreted without consideration of clinical factors.

Research at our institution and others has shown that acidemia is more significantly associated with non-NICHD measures of fetal heart rate deceleration than with each of the main deceleration types defined by the 2008 NICHD system (i.e., repetitive variable, repetitive late, and repetitive prolonged).

For instance, Emily Hamilton, MD, and her colleagues at PeriGen, a perinatal software company, found that only prolonged decelerations, in addition to the variability within the deceleration and a depth below 60 beats per minute for more than 60 seconds, could discriminate between cases of metabolic acidosis and those with normal umbilical artery gases (J Matern Fetal Neonatal Med. 2012 Jun;25[6]:648-53).

In a 4-year retrospective cohort study of nearly 5,340 consecutive singleton, term, nonanomalous gestations, we found acidemia was most significantly associated with a calculation of the “total deceleration area” – the sum of the estimates of area within all the decelerations. This measure accounted for the frequency, depth, and duration of all decelerations in the final 30 minutes of EFM.

Each of the NICHD deceleration types was associated in our study with acidemia after adjustment for fever, obesity, prolonged first stage, and nulliparity. However, total deceleration area had superior predictive ability. After the same adjustments were made, an abnormal total deceleration area (greater than the 95th percentile) was significantly associated with an increased risk for acidemia (odds ratio, 3.79) (Am J Obstet Gynecol. 2012 Sep;207[3]:206.e1-8).

Pathophysiologically, it seems logical that the total area is most predictive, as it captures both the temporal and dose effect of decelerations. At this point, however, we can only apply this concept crudely at the bedside. There is more work to do to translate such findings into software-driven bedside tools.

Gaining reassurance

Although efforts to manage intrapartum fetal heart rate tracings focus largely on attempting to better predict who is at greatest risk for acidemia, it is important and worthwhile that we also attempt to determine whether a fetus with a category II tracing is not acidotic.

Research has consistently shown that the presence of accelerations, whether spontaneous or stimulated, is a highly reliable indicator of normal neonatal umbilical cord pH. It is therefore reasonable, when faced with indeterminate tracings (e.g., minimal variability), to consider scalp stimulation to elicit fetal heart rate acceleration. Scalp stimulation is the easiest noninvasive tool to employ to quickly secure clinical reassurance – within a couple of minutes – that the fetus is not acidotic.

For guidance on managing repetitive variable decelerations, amnioinfusion with normal saline is similarly worthy of consideration. It has been demonstrated (Level A evidence) to resolve variable fetal heart rate decelerations and reduce the incidence of cesarean delivery for nonreassuring fetal heart rate patterns. Both amnioinfusion and scalp stimulation are recommended in the 2014 ACOG/SMFM consensus statement on “Safe Prevention of the Primary Cesarean Delivery” (Obstet Gynecol. 2014 Mar;123[3]:693-711).

Oxygen administration, on the other hand, is ingrained in practice and is included in the American College of Obstetricians and Gynecologists’ practice bulletin on managing intrapartum fetal rate tracings. It is listed as a possible resuscitative measure for category II or III tracings, despite the fact that there are extremely limited data for its effectiveness or safety in labor.

Maureen S. Hamel, MD, and her colleagues at the Warren Albert Medical School at Brown University reviewed the literature and concluded that the only two randomized trials investigating the use of maternal oxygen supplementation in laboring women do not support the idea that supplementation may benefit the fetus. Moreover, they contended that oxygen supplementation may even be harmful (Am J Obstet Gynecol. 2014 Aug;211[2]:124-7).

If supplemental oxygen were a medication, we would want to know the dose, as well as the length and duration of administration before fetal heart rate tracing improved. We don’t know the answers to these questions.

There is research ongoing, both observational studies and at least one registered randomized clinical trial, that should provide more information and guidance on the impact of supplemental oxygen in the setting of category II fetal heart rate patterns. I do not expect these findings to resolve all the questions. We’re going to need a thorough body of work to provide us with definitive answers.
 

Dr. Cahill is the chief of the division of maternal-fetal medicine at Washington University in St. Louis. She reported having no financial disclosures relevant to this Master Class.

There is no question that we are living in the information age where “big data” isn’t just reserved for scientists but is accessible to everyone. Wearable devices have revolutionized when and how often we exercise. Smartphones have changed the way in which we consume news, watch television, take photographs, and record home movies. Online video chatting has allowed people who live miles – or even countries – away to connect on a whole new level. Today’s 7-year-olds have never lived in a world without iPhones and don’t know what life is like without iPads. Technology has improved our daily lives in countless ways. However, is “too much of a good thing” ever just too much?

Last year, we looked back over the preceding 5 decades of ob.gyn. practice. This retrospective analysis demonstrated that today’s practitioners have infinitely more tools at their disposal than many of their mentors did to ensure the best pregnancy outcomes. From prenatal diagnostic approaches, such as ultrasonography and genetic screening, to in utero surgical interventions, our discipline has advanced in leaps and bounds, all over the course of one person’s lifetime.

Dr. Reece, who specializes in maternal-fetal medicine, is vice president for medical affairs at the University of Maryland, Baltimore, as well as the John Z. and Akiko K. Bowers Distinguished Professor and dean of the school of medicine. Dr. Reece said he had no relevant financial disclosures. He is the medical editor of this column. Contact him at [email protected].

There is no question that we are living in the information age where “big data” isn’t just reserved for scientists but is accessible to everyone. Wearable devices have revolutionized when and how often we exercise. Smartphones have changed the way in which we consume news, watch television, take photographs, and record home movies. Online video chatting has allowed people who live miles – or even countries – away to connect on a whole new level. Today’s 7-year-olds have never lived in a world without iPhones and don’t know what life is like without iPads. Technology has improved our daily lives in countless ways. However, is “too much of a good thing” ever just too much?

Last year, we looked back over the preceding 5 decades of ob.gyn. practice. This retrospective analysis demonstrated that today’s practitioners have infinitely more tools at their disposal than many of their mentors did to ensure the best pregnancy outcomes. From prenatal diagnostic approaches, such as ultrasonography and genetic screening, to in utero surgical interventions, our discipline has advanced in leaps and bounds, all over the course of one person’s lifetime.

Dr. Reece, who specializes in maternal-fetal medicine, is vice president for medical affairs at the University of Maryland, Baltimore, as well as the John Z. and Akiko K. Bowers Distinguished Professor and dean of the school of medicine. Dr. Reece said he had no relevant financial disclosures. He is the medical editor of this column. Contact him at [email protected].

There is no question that we are living in the information age where “big data” isn’t just reserved for scientists but is accessible to everyone. Wearable devices have revolutionized when and how often we exercise. Smartphones have changed the way in which we consume news, watch television, take photographs, and record home movies. Online video chatting has allowed people who live miles – or even countries – away to connect on a whole new level. Today’s 7-year-olds have never lived in a world without iPhones and don’t know what life is like without iPads. Technology has improved our daily lives in countless ways. However, is “too much of a good thing” ever just too much?

Last year, we looked back over the preceding 5 decades of ob.gyn. practice. This retrospective analysis demonstrated that today’s practitioners have infinitely more tools at their disposal than many of their mentors did to ensure the best pregnancy outcomes. From prenatal diagnostic approaches, such as ultrasonography and genetic screening, to in utero surgical interventions, our discipline has advanced in leaps and bounds, all over the course of one person’s lifetime.

Dr. Reece, who specializes in maternal-fetal medicine, is vice president for medical affairs at the University of Maryland, Baltimore, as well as the John Z. and Akiko K. Bowers Distinguished Professor and dean of the school of medicine. Dr. Reece said he had no relevant financial disclosures. He is the medical editor of this column. Contact him at [email protected].

The Food and Drug Administration approved 22 new drug products in 12 pharmacologic classes in 2016. Additionally, daclizumab (Zenapax), which was approved several years ago for prophylaxis of acute organ rejection in patients receiving renal transplants, was approved for multiple sclerosis treatment (Zinbryta) last year, and sofosbuvir (Sovaldi), which was approved in 2013 for the treatment of hepatitis C virus, is now combined with velpatasvir (Epclusa) to treat all six major forms of hepatitis C.

There are 22 drugs that can be considered novel drugs. As defined by the FDA, novel drugs have never been approved for human use. There are no human pregnancy data for any of the newly approved drugs or drug combinations. As such, it is important to consider that high molecular weight drugs that probably do not cross the placenta in the first half of pregnancy may do so in late pregnancy.

Antineoplastics

Atezolizumab (Tecentriq) is a programmed death ligand–blocking antibody that is indicated for locally advanced or metastatic urothelial carcinoma and metastatic nonsmall cell lung cancer following platinum-containing chemotherapy. Animal reproduction studies have not been conducted, but, based on its mechanism of action, fetal exposure may increase the risk of developing immune-mediated disorders or altering the normal immune response. The molecular weight is high (145,000) and the terminal half-life is long (27 days).

Olaratumab (Lartruvo) is a platelet-derived growth factor receptor– alpha-blocking antibody. It is indicated, in combination with doxorubicin, for the treatment of soft tissue sarcoma. Although the estimated elimination half-life is long (about 11 days with a range of 6-24 days), the high molecular weight (about 154,000) should limit fetal exposure, at least in the first half of pregnancy. The drug should be avoided in pregnancy, however, based on the animal data, the mechanism of action, and its combination with doxorubicin.

Rucaparib (Rubraca) is a poly (adenosine diphosphate–ribose) polymerase inhibitor indicated for the treatment of ovarian cancer. The drug could cause human fetal harm based on the animal data, mechanism of action, relatively low molecular weight (about 556), and terminal half-life (17 hours).

Venetoclax (Venclexta) is a B-cell lymphoma 2 inhibitor indicated for the treatment of chronic lymphocytic leukemia. Although the animal data, molecular weight (about 868), and elimination half-life (about 26 hours) suggest embryo-fetal risk, the high plasma protein binding (99.9%) should limit the amount crossing the placenta.

Anti-infectives

There are two new monoclonal antibodies in this class. Bezlotoxumab (Zinplava) is used to reduce recurrence of Clostridium difficile. Animal reproduction studies have not been conducted. As the molecular weight is about 148,000, the drug will not cross the placenta, at least not in the first half of pregnancy. However, the drug has a long elimination half-life (about 19 days), so, depending on when it was given, it could cross in late pregnancy. Obiltoxaximab (Anthim), administered as a single IV dose, is indicated for the treatment of inhaled anthrax due to Bacillus anthracis. No fetal harm was observed in animal reproduction studies. The high molecular weight (about 148,000) suggests that the drug will not cross to the embryo and/or fetus, at least not in the first part of pregnancy.

Elbasvir/Grazoprevir (Zepatier) is indicated for the treatment of chronic hepatitis C virus genotype 1 or 4. Animal reproduction studies found no evidence of adverse developmental outcomes. The molecular weights of the two components are about 882 and 767, respectively. Both are extensively bound to plasma proteins, 99.9% and 98.8%, respectively, and the terminal half-lives are 24 and 31 hours. Thus, the product appears to be low risk if used in human pregnancy. However, it is contraindicated if given with ribavirin.

moodboard/Thinkstock

Central nervous system agents

Brivaracetam (Briviact) is an anticonvulsant used to treat partial-onset seizures. Animal reproduction studies suggest moderate risk. The molecular weight (about 212), low plasma protein binding (less than or equal to 20%), and terminal plasma half-life of about 9 hours suggest that the drug will cross the placenta. The manufacturer recommends that the drug should be used in pregnancy only if the potential benefit justifies the potential risk to the embryo/fetus.

Pimavanserin (Nuplazid) is an atypical antipsychotic indicated for the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis. Reproduction studies in animals suggest low risk. The molecular weight of the free base (about 428) and the long mean plasma half-lives of the parent drug and active metabolite (57 and 200 hours) suggest that the drug will cross the placenta. However, the high plasma protein binding (about 95%) may limit the exposure. Nevertheless, avoiding the period of organogenesis appears to be best.

Dermatologic agents

Crisaborole (Eucrisa) is indicated for topical treatment of mild to moderate atopic dermatitis. In 33 pediatric subjects (aged 2-17 years) who applied the ointment twice daily for 8 days, low amounts were absorbed systemically with plasma concentrations in the nanogram/milliliter range. Plasma protein binding was 97%. With oral formulations of the drug, animal reproduction studies suggest low risk. Taken in sum, the human pregnancy risk appears to be low.

Ixekizumab (Taltz) is a humanized interleukin-17A antagonist, administered subcutaneously, that is indicated for the treatment of adults with moderate to severe plaque psoriasis. The drug did not cause developmental toxicity in monkeys. The molecular weight for the drug’s protein backbone is 146,158, and the mean elimination half-life was 13 days. The human embryo-fetal risk in the first half of pregnancy appears to be low.

Diagnostic agents

Fluciclovine F 18 (Axumin) is a radioactive diagnostic agent indicated for positron emission tomography imaging in men with suspected prostate cancer. Since the agent is only used in men, there are no human or animal pregnancy data.

Gallium GA 68 dotatate injection, a diagnostic imaging agent to detect rare neuroendocrine tumors, is not yet on the market.

Endocrine/metabolic agents

Lixisenatide (Adlyxin) is a glucagon-like–peptide-1 receptor agonist that is administered subcutaneously. It is indicated as an adjunct to diet and exercise to improve glycemic control in type 2 diabetes. The drug was teratogenic in two animal species. The molecular weight is about 4,859, and the mean terminal half-life was about 3 hours. Since tight control of glucose levels in type 2 diabetes is required during pregnancy, insulin is the treatment of choice. Consequently, lixisenatide should not be used during pregnancy.

Gastrointestinal agents

Obeticholic acid (Ocaliva) is a farnesoid X receptor agonist that is given orally for the treatment of primary biliary cholangitis, in combination with ursodiol, or ursodeoxycholic acid. I have classified ursodiol as compatible in pregnancy in the 10th edition of “Drugs in Pregnancy and Lactation” (2011: Wolters Kluwer Health). The animal reproduction data for both drugs suggest low risk. Based on the molecular weight of obeticholic (about 421), the drug will probably cross to the embryo/fetus, but the high plasma protein binding (greater than 99%) may limit exposure. The elimination half-life is apparently unknown.

Hematologic agents

Defibrotide sodium (Defitelio), given as an intravenous infusion, is an oligonucleotide mixture. It is indicated for the treatment of hepatic veno-occlusive disease, also known as sinusoidal obstruction syndrome, with renal or pulmonary dysfunction following hematopoietic stem-cell transplantation. Animal reproduction studies in two species suggest risk. The mean molecular weight is 13,000-20,000. Plasma protein binding is an average 93%, and the elimination half-life is less than 2 hours. It is doubtful if the drug crosses the placenta, especially in the first half of pregnancy. If possible, avoid the drug in the second half of pregnancy.

Immunologics

Two indications have been approved for daclizumab. The first was in 2005 for the prophylaxis of acute organ rejection of renal transplants (Zenapax), and the second was in 2016 for the treatment of relapsing forms of multiple sclerosis (Zinbryta). Reproduction studies in monkeys with Zinbryta can be classified as low risk. The molecular weight (about 144,000) suggests that the drug will not cross the placenta, at least in the first half of pregnancy. However, depending on when the drug is given, the long elimination half-life of 21 days might allow the drug to cross in late pregnancy. Regardless, if the perceived maternal benefit exceeds the potential embryo-fetal risk, the drug should not be withheld because of pregnancy.

Muscular disorder agents

Eteplirsen (Exondys 51) is an antisense oligonucleotide that is given intravenously. It is indicated for the treatment of Duchenne muscular dystrophy in patients who have a confirmed mutation of the related gene, which is amenable to exon 51 skipping. There are no animal reproduction data. The molecular weight is about 10,306. This suggests that the drug will not cross the placenta, at least in the first half of pregnancy. The elimination half-life is 3-4 hours, and the plasma concentration 24 hours after a dose was 0.07% of the peak plasma concentration. The drug is given once weekly, and waiting for 24 hours or slightly longer after a dose should reduce the exposure, if any, of the embryo-fetus during the first half of pregnancy.

Nusinersen (Spinraza), a survival motor neuron 2 directed–antisense oligonucleotide, is given as an intrathecal dose. It is indicated for the treatment of spinal muscular atrophy. Subcutaneous doses in two animal species caused no developmental toxicity. The molecular weight of 7,501 suggests that the drug will not cross the human placenta, at least not in the first half of pregnancy. The mean terminal elimination half-life in cerebrospinal fluid was 135-177 days and 63-87 days in plasma.

Ophthalmic agents

Lifitegrast (Xiidra) is an ophthalmic solution of a lymphocyte function-associated–antigen-1 antagonist. It is indicated for the treatment of the signs and symptoms of dry eye disease. The animal reproduction data suggest low risk. The molecular weight is about 616, suggesting that the drug would cross the placenta. However, in a Phase III trial conducted before FDA approval, 47 patients with dry eye disease were given 1 drop twice daily for periods up to 360 days. Nine patients (19%) had plasma predose (trough) concentrations above 0.5 ng/mL, the lower limit of quantitation. Trough plasma concentrations in these patients ranged from 0.55 ng/mL to 3.74 ng/mL. These amounts do not appear to represent an embryo-fetal risk.

Respiratory agents

Reslizumab (Cinqair), an interleukin-5 antagonist monoclonal antibody, is given intravenously. It is indicated for add-on maintenance treatment of severe asthma in patients with an eosinophilic phenotype. Animal data in two species suggest low risk. The molecular weight is about 147,000, and the elimination half-life is about 24 days. This suggests that exposure of the embryo and fetus will be minimal, at least in the first half of pregnancy. The maternal benefit appears to outweigh the unknown embryo-fetal risk.

Lactation

None of the above drugs have been studied during breastfeeding. Many drugs, regardless of their molecular weight, will cross into milk in small amounts during the first postpartum week. The effects of this exposure on a nursing infant are unknown. Based on the potential for nursing infant harm, the drugs that probably should not be given during breastfeeding include the four antineoplastics, the atypical antipsychotic pimavanserin, and the diabetes injection lixisenatide.

Mr. Briggs is a clinical professor of pharmacy at the University of California, San Francisco, and an adjunct professor of pharmacy at the University of Southern California, Los Angeles, and at Washington State University, Spokane. He coauthored “Drugs in Pregnancy and Lactation,” and coedited “Diseases, Complications, and Drug Therapy in Obstetrics.” He reported having no relevant financial disclosures.

The Food and Drug Administration approved 22 new drug products in 12 pharmacologic classes in 2016. Additionally, daclizumab (Zenapax), which was approved several years ago for prophylaxis of acute organ rejection in patients receiving renal transplants, was approved for multiple sclerosis treatment (Zinbryta) last year, and sofosbuvir (Sovaldi), which was approved in 2013 for the treatment of hepatitis C virus, is now combined with velpatasvir (Epclusa) to treat all six major forms of hepatitis C.

There are 22 drugs that can be considered novel drugs. As defined by the FDA, novel drugs have never been approved for human use. There are no human pregnancy data for any of the newly approved drugs or drug combinations. As such, it is important to consider that high molecular weight drugs that probably do not cross the placenta in the first half of pregnancy may do so in late pregnancy.

Antineoplastics

Atezolizumab (Tecentriq) is a programmed death ligand–blocking antibody that is indicated for locally advanced or metastatic urothelial carcinoma and metastatic nonsmall cell lung cancer following platinum-containing chemotherapy. Animal reproduction studies have not been conducted, but, based on its mechanism of action, fetal exposure may increase the risk of developing immune-mediated disorders or altering the normal immune response. The molecular weight is high (145,000) and the terminal half-life is long (27 days).

Olaratumab (Lartruvo) is a platelet-derived growth factor receptor– alpha-blocking antibody. It is indicated, in combination with doxorubicin, for the treatment of soft tissue sarcoma. Although the estimated elimination half-life is long (about 11 days with a range of 6-24 days), the high molecular weight (about 154,000) should limit fetal exposure, at least in the first half of pregnancy. The drug should be avoided in pregnancy, however, based on the animal data, the mechanism of action, and its combination with doxorubicin.

Rucaparib (Rubraca) is a poly (adenosine diphosphate–ribose) polymerase inhibitor indicated for the treatment of ovarian cancer. The drug could cause human fetal harm based on the animal data, mechanism of action, relatively low molecular weight (about 556), and terminal half-life (17 hours).

Venetoclax (Venclexta) is a B-cell lymphoma 2 inhibitor indicated for the treatment of chronic lymphocytic leukemia. Although the animal data, molecular weight (about 868), and elimination half-life (about 26 hours) suggest embryo-fetal risk, the high plasma protein binding (99.9%) should limit the amount crossing the placenta.

Anti-infectives

There are two new monoclonal antibodies in this class. Bezlotoxumab (Zinplava) is used to reduce recurrence of Clostridium difficile. Animal reproduction studies have not been conducted. As the molecular weight is about 148,000, the drug will not cross the placenta, at least not in the first half of pregnancy. However, the drug has a long elimination half-life (about 19 days), so, depending on when it was given, it could cross in late pregnancy. Obiltoxaximab (Anthim), administered as a single IV dose, is indicated for the treatment of inhaled anthrax due to Bacillus anthracis. No fetal harm was observed in animal reproduction studies. The high molecular weight (about 148,000) suggests that the drug will not cross to the embryo and/or fetus, at least not in the first part of pregnancy.

Elbasvir/Grazoprevir (Zepatier) is indicated for the treatment of chronic hepatitis C virus genotype 1 or 4. Animal reproduction studies found no evidence of adverse developmental outcomes. The molecular weights of the two components are about 882 and 767, respectively. Both are extensively bound to plasma proteins, 99.9% and 98.8%, respectively, and the terminal half-lives are 24 and 31 hours. Thus, the product appears to be low risk if used in human pregnancy. However, it is contraindicated if given with ribavirin.

moodboard/Thinkstock

Central nervous system agents

Brivaracetam (Briviact) is an anticonvulsant used to treat partial-onset seizures. Animal reproduction studies suggest moderate risk. The molecular weight (about 212), low plasma protein binding (less than or equal to 20%), and terminal plasma half-life of about 9 hours suggest that the drug will cross the placenta. The manufacturer recommends that the drug should be used in pregnancy only if the potential benefit justifies the potential risk to the embryo/fetus.

Pimavanserin (Nuplazid) is an atypical antipsychotic indicated for the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis. Reproduction studies in animals suggest low risk. The molecular weight of the free base (about 428) and the long mean plasma half-lives of the parent drug and active metabolite (57 and 200 hours) suggest that the drug will cross the placenta. However, the high plasma protein binding (about 95%) may limit the exposure. Nevertheless, avoiding the period of organogenesis appears to be best.

Dermatologic agents

Crisaborole (Eucrisa) is indicated for topical treatment of mild to moderate atopic dermatitis. In 33 pediatric subjects (aged 2-17 years) who applied the ointment twice daily for 8 days, low amounts were absorbed systemically with plasma concentrations in the nanogram/milliliter range. Plasma protein binding was 97%. With oral formulations of the drug, animal reproduction studies suggest low risk. Taken in sum, the human pregnancy risk appears to be low.

Ixekizumab (Taltz) is a humanized interleukin-17A antagonist, administered subcutaneously, that is indicated for the treatment of adults with moderate to severe plaque psoriasis. The drug did not cause developmental toxicity in monkeys. The molecular weight for the drug’s protein backbone is 146,158, and the mean elimination half-life was 13 days. The human embryo-fetal risk in the first half of pregnancy appears to be low.

Diagnostic agents

Fluciclovine F 18 (Axumin) is a radioactive diagnostic agent indicated for positron emission tomography imaging in men with suspected prostate cancer. Since the agent is only used in men, there are no human or animal pregnancy data.

Gallium GA 68 dotatate injection, a diagnostic imaging agent to detect rare neuroendocrine tumors, is not yet on the market.

Endocrine/metabolic agents

Lixisenatide (Adlyxin) is a glucagon-like–peptide-1 receptor agonist that is administered subcutaneously. It is indicated as an adjunct to diet and exercise to improve glycemic control in type 2 diabetes. The drug was teratogenic in two animal species. The molecular weight is about 4,859, and the mean terminal half-life was about 3 hours. Since tight control of glucose levels in type 2 diabetes is required during pregnancy, insulin is the treatment of choice. Consequently, lixisenatide should not be used during pregnancy.

Gastrointestinal agents

Obeticholic acid (Ocaliva) is a farnesoid X receptor agonist that is given orally for the treatment of primary biliary cholangitis, in combination with ursodiol, or ursodeoxycholic acid. I have classified ursodiol as compatible in pregnancy in the 10th edition of “Drugs in Pregnancy and Lactation” (2011: Wolters Kluwer Health). The animal reproduction data for both drugs suggest low risk. Based on the molecular weight of obeticholic (about 421), the drug will probably cross to the embryo/fetus, but the high plasma protein binding (greater than 99%) may limit exposure. The elimination half-life is apparently unknown.

Hematologic agents

Defibrotide sodium (Defitelio), given as an intravenous infusion, is an oligonucleotide mixture. It is indicated for the treatment of hepatic veno-occlusive disease, also known as sinusoidal obstruction syndrome, with renal or pulmonary dysfunction following hematopoietic stem-cell transplantation. Animal reproduction studies in two species suggest risk. The mean molecular weight is 13,000-20,000. Plasma protein binding is an average 93%, and the elimination half-life is less than 2 hours. It is doubtful if the drug crosses the placenta, especially in the first half of pregnancy. If possible, avoid the drug in the second half of pregnancy.

Immunologics

Two indications have been approved for daclizumab. The first was in 2005 for the prophylaxis of acute organ rejection of renal transplants (Zenapax), and the second was in 2016 for the treatment of relapsing forms of multiple sclerosis (Zinbryta). Reproduction studies in monkeys with Zinbryta can be classified as low risk. The molecular weight (about 144,000) suggests that the drug will not cross the placenta, at least in the first half of pregnancy. However, depending on when the drug is given, the long elimination half-life of 21 days might allow the drug to cross in late pregnancy. Regardless, if the perceived maternal benefit exceeds the potential embryo-fetal risk, the drug should not be withheld because of pregnancy.

Muscular disorder agents

Eteplirsen (Exondys 51) is an antisense oligonucleotide that is given intravenously. It is indicated for the treatment of Duchenne muscular dystrophy in patients who have a confirmed mutation of the related gene, which is amenable to exon 51 skipping. There are no animal reproduction data. The molecular weight is about 10,306. This suggests that the drug will not cross the placenta, at least in the first half of pregnancy. The elimination half-life is 3-4 hours, and the plasma concentration 24 hours after a dose was 0.07% of the peak plasma concentration. The drug is given once weekly, and waiting for 24 hours or slightly longer after a dose should reduce the exposure, if any, of the embryo-fetus during the first half of pregnancy.

Nusinersen (Spinraza), a survival motor neuron 2 directed–antisense oligonucleotide, is given as an intrathecal dose. It is indicated for the treatment of spinal muscular atrophy. Subcutaneous doses in two animal species caused no developmental toxicity. The molecular weight of 7,501 suggests that the drug will not cross the human placenta, at least not in the first half of pregnancy. The mean terminal elimination half-life in cerebrospinal fluid was 135-177 days and 63-87 days in plasma.

Ophthalmic agents

Lifitegrast (Xiidra) is an ophthalmic solution of a lymphocyte function-associated–antigen-1 antagonist. It is indicated for the treatment of the signs and symptoms of dry eye disease. The animal reproduction data suggest low risk. The molecular weight is about 616, suggesting that the drug would cross the placenta. However, in a Phase III trial conducted before FDA approval, 47 patients with dry eye disease were given 1 drop twice daily for periods up to 360 days. Nine patients (19%) had plasma predose (trough) concentrations above 0.5 ng/mL, the lower limit of quantitation. Trough plasma concentrations in these patients ranged from 0.55 ng/mL to 3.74 ng/mL. These amounts do not appear to represent an embryo-fetal risk.

Respiratory agents

Reslizumab (Cinqair), an interleukin-5 antagonist monoclonal antibody, is given intravenously. It is indicated for add-on maintenance treatment of severe asthma in patients with an eosinophilic phenotype. Animal data in two species suggest low risk. The molecular weight is about 147,000, and the elimination half-life is about 24 days. This suggests that exposure of the embryo and fetus will be minimal, at least in the first half of pregnancy. The maternal benefit appears to outweigh the unknown embryo-fetal risk.

Lactation

None of the above drugs have been studied during breastfeeding. Many drugs, regardless of their molecular weight, will cross into milk in small amounts during the first postpartum week. The effects of this exposure on a nursing infant are unknown. Based on the potential for nursing infant harm, the drugs that probably should not be given during breastfeeding include the four antineoplastics, the atypical antipsychotic pimavanserin, and the diabetes injection lixisenatide.

Mr. Briggs is a clinical professor of pharmacy at the University of California, San Francisco, and an adjunct professor of pharmacy at the University of Southern California, Los Angeles, and at Washington State University, Spokane. He coauthored “Drugs in Pregnancy and Lactation,” and coedited “Diseases, Complications, and Drug Therapy in Obstetrics.” He reported having no relevant financial disclosures.

The Food and Drug Administration approved 22 new drug products in 12 pharmacologic classes in 2016. Additionally, daclizumab (Zenapax), which was approved several years ago for prophylaxis of acute organ rejection in patients receiving renal transplants, was approved for multiple sclerosis treatment (Zinbryta) last year, and sofosbuvir (Sovaldi), which was approved in 2013 for the treatment of hepatitis C virus, is now combined with velpatasvir (Epclusa) to treat all six major forms of hepatitis C.

There are 22 drugs that can be considered novel drugs. As defined by the FDA, novel drugs have never been approved for human use. There are no human pregnancy data for any of the newly approved drugs or drug combinations. As such, it is important to consider that high molecular weight drugs that probably do not cross the placenta in the first half of pregnancy may do so in late pregnancy.

Antineoplastics

Atezolizumab (Tecentriq) is a programmed death ligand–blocking antibody that is indicated for locally advanced or metastatic urothelial carcinoma and metastatic nonsmall cell lung cancer following platinum-containing chemotherapy. Animal reproduction studies have not been conducted, but, based on its mechanism of action, fetal exposure may increase the risk of developing immune-mediated disorders or altering the normal immune response. The molecular weight is high (145,000) and the terminal half-life is long (27 days).

Olaratumab (Lartruvo) is a platelet-derived growth factor receptor– alpha-blocking antibody. It is indicated, in combination with doxorubicin, for the treatment of soft tissue sarcoma. Although the estimated elimination half-life is long (about 11 days with a range of 6-24 days), the high molecular weight (about 154,000) should limit fetal exposure, at least in the first half of pregnancy. The drug should be avoided in pregnancy, however, based on the animal data, the mechanism of action, and its combination with doxorubicin.

Rucaparib (Rubraca) is a poly (adenosine diphosphate–ribose) polymerase inhibitor indicated for the treatment of ovarian cancer. The drug could cause human fetal harm based on the animal data, mechanism of action, relatively low molecular weight (about 556), and terminal half-life (17 hours).

Venetoclax (Venclexta) is a B-cell lymphoma 2 inhibitor indicated for the treatment of chronic lymphocytic leukemia. Although the animal data, molecular weight (about 868), and elimination half-life (about 26 hours) suggest embryo-fetal risk, the high plasma protein binding (99.9%) should limit the amount crossing the placenta.

Anti-infectives

There are two new monoclonal antibodies in this class. Bezlotoxumab (Zinplava) is used to reduce recurrence of Clostridium difficile. Animal reproduction studies have not been conducted. As the molecular weight is about 148,000, the drug will not cross the placenta, at least not in the first half of pregnancy. However, the drug has a long elimination half-life (about 19 days), so, depending on when it was given, it could cross in late pregnancy. Obiltoxaximab (Anthim), administered as a single IV dose, is indicated for the treatment of inhaled anthrax due to Bacillus anthracis. No fetal harm was observed in animal reproduction studies. The high molecular weight (about 148,000) suggests that the drug will not cross to the embryo and/or fetus, at least not in the first part of pregnancy.

Elbasvir/Grazoprevir (Zepatier) is indicated for the treatment of chronic hepatitis C virus genotype 1 or 4. Animal reproduction studies found no evidence of adverse developmental outcomes. The molecular weights of the two components are about 882 and 767, respectively. Both are extensively bound to plasma proteins, 99.9% and 98.8%, respectively, and the terminal half-lives are 24 and 31 hours. Thus, the product appears to be low risk if used in human pregnancy. However, it is contraindicated if given with ribavirin.

moodboard/Thinkstock

Central nervous system agents

Brivaracetam (Briviact) is an anticonvulsant used to treat partial-onset seizures. Animal reproduction studies suggest moderate risk. The molecular weight (about 212), low plasma protein binding (less than or equal to 20%), and terminal plasma half-life of about 9 hours suggest that the drug will cross the placenta. The manufacturer recommends that the drug should be used in pregnancy only if the potential benefit justifies the potential risk to the embryo/fetus.

Pimavanserin (Nuplazid) is an atypical antipsychotic indicated for the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis. Reproduction studies in animals suggest low risk. The molecular weight of the free base (about 428) and the long mean plasma half-lives of the parent drug and active metabolite (57 and 200 hours) suggest that the drug will cross the placenta. However, the high plasma protein binding (about 95%) may limit the exposure. Nevertheless, avoiding the period of organogenesis appears to be best.

Dermatologic agents

Crisaborole (Eucrisa) is indicated for topical treatment of mild to moderate atopic dermatitis. In 33 pediatric subjects (aged 2-17 years) who applied the ointment twice daily for 8 days, low amounts were absorbed systemically with plasma concentrations in the nanogram/milliliter range. Plasma protein binding was 97%. With oral formulations of the drug, animal reproduction studies suggest low risk. Taken in sum, the human pregnancy risk appears to be low.

Ixekizumab (Taltz) is a humanized interleukin-17A antagonist, administered subcutaneously, that is indicated for the treatment of adults with moderate to severe plaque psoriasis. The drug did not cause developmental toxicity in monkeys. The molecular weight for the drug’s protein backbone is 146,158, and the mean elimination half-life was 13 days. The human embryo-fetal risk in the first half of pregnancy appears to be low.

Diagnostic agents

Fluciclovine F 18 (Axumin) is a radioactive diagnostic agent indicated for positron emission tomography imaging in men with suspected prostate cancer. Since the agent is only used in men, there are no human or animal pregnancy data.

Gallium GA 68 dotatate injection, a diagnostic imaging agent to detect rare neuroendocrine tumors, is not yet on the market.

Endocrine/metabolic agents

Lixisenatide (Adlyxin) is a glucagon-like–peptide-1 receptor agonist that is administered subcutaneously. It is indicated as an adjunct to diet and exercise to improve glycemic control in type 2 diabetes. The drug was teratogenic in two animal species. The molecular weight is about 4,859, and the mean terminal half-life was about 3 hours. Since tight control of glucose levels in type 2 diabetes is required during pregnancy, insulin is the treatment of choice. Consequently, lixisenatide should not be used during pregnancy.

Gastrointestinal agents

Obeticholic acid (Ocaliva) is a farnesoid X receptor agonist that is given orally for the treatment of primary biliary cholangitis, in combination with ursodiol, or ursodeoxycholic acid. I have classified ursodiol as compatible in pregnancy in the 10th edition of “Drugs in Pregnancy and Lactation” (2011: Wolters Kluwer Health). The animal reproduction data for both drugs suggest low risk. Based on the molecular weight of obeticholic (about 421), the drug will probably cross to the embryo/fetus, but the high plasma protein binding (greater than 99%) may limit exposure. The elimination half-life is apparently unknown.

Hematologic agents

Defibrotide sodium (Defitelio), given as an intravenous infusion, is an oligonucleotide mixture. It is indicated for the treatment of hepatic veno-occlusive disease, also known as sinusoidal obstruction syndrome, with renal or pulmonary dysfunction following hematopoietic stem-cell transplantation. Animal reproduction studies in two species suggest risk. The mean molecular weight is 13,000-20,000. Plasma protein binding is an average 93%, and the elimination half-life is less than 2 hours. It is doubtful if the drug crosses the placenta, especially in the first half of pregnancy. If possible, avoid the drug in the second half of pregnancy.

Immunologics

Two indications have been approved for daclizumab. The first was in 2005 for the prophylaxis of acute organ rejection of renal transplants (Zenapax), and the second was in 2016 for the treatment of relapsing forms of multiple sclerosis (Zinbryta). Reproduction studies in monkeys with Zinbryta can be classified as low risk. The molecular weight (about 144,000) suggests that the drug will not cross the placenta, at least in the first half of pregnancy. However, depending on when the drug is given, the long elimination half-life of 21 days might allow the drug to cross in late pregnancy. Regardless, if the perceived maternal benefit exceeds the potential embryo-fetal risk, the drug should not be withheld because of pregnancy.

Muscular disorder agents

Eteplirsen (Exondys 51) is an antisense oligonucleotide that is given intravenously. It is indicated for the treatment of Duchenne muscular dystrophy in patients who have a confirmed mutation of the related gene, which is amenable to exon 51 skipping. There are no animal reproduction data. The molecular weight is about 10,306. This suggests that the drug will not cross the placenta, at least in the first half of pregnancy. The elimination half-life is 3-4 hours, and the plasma concentration 24 hours after a dose was 0.07% of the peak plasma concentration. The drug is given once weekly, and waiting for 24 hours or slightly longer after a dose should reduce the exposure, if any, of the embryo-fetus during the first half of pregnancy.

Nusinersen (Spinraza), a survival motor neuron 2 directed–antisense oligonucleotide, is given as an intrathecal dose. It is indicated for the treatment of spinal muscular atrophy. Subcutaneous doses in two animal species caused no developmental toxicity. The molecular weight of 7,501 suggests that the drug will not cross the human placenta, at least not in the first half of pregnancy. The mean terminal elimination half-life in cerebrospinal fluid was 135-177 days and 63-87 days in plasma.

Ophthalmic agents

Lifitegrast (Xiidra) is an ophthalmic solution of a lymphocyte function-associated–antigen-1 antagonist. It is indicated for the treatment of the signs and symptoms of dry eye disease. The animal reproduction data suggest low risk. The molecular weight is about 616, suggesting that the drug would cross the placenta. However, in a Phase III trial conducted before FDA approval, 47 patients with dry eye disease were given 1 drop twice daily for periods up to 360 days. Nine patients (19%) had plasma predose (trough) concentrations above 0.5 ng/mL, the lower limit of quantitation. Trough plasma concentrations in these patients ranged from 0.55 ng/mL to 3.74 ng/mL. These amounts do not appear to represent an embryo-fetal risk.

Respiratory agents

Reslizumab (Cinqair), an interleukin-5 antagonist monoclonal antibody, is given intravenously. It is indicated for add-on maintenance treatment of severe asthma in patients with an eosinophilic phenotype. Animal data in two species suggest low risk. The molecular weight is about 147,000, and the elimination half-life is about 24 days. This suggests that exposure of the embryo and fetus will be minimal, at least in the first half of pregnancy. The maternal benefit appears to outweigh the unknown embryo-fetal risk.

Lactation

None of the above drugs have been studied during breastfeeding. Many drugs, regardless of their molecular weight, will cross into milk in small amounts during the first postpartum week. The effects of this exposure on a nursing infant are unknown. Based on the potential for nursing infant harm, the drugs that probably should not be given during breastfeeding include the four antineoplastics, the atypical antipsychotic pimavanserin, and the diabetes injection lixisenatide.

Mr. Briggs is a clinical professor of pharmacy at the University of California, San Francisco, and an adjunct professor of pharmacy at the University of Southern California, Los Angeles, and at Washington State University, Spokane. He coauthored “Drugs in Pregnancy and Lactation,” and coedited “Diseases, Complications, and Drug Therapy in Obstetrics.” He reported having no relevant financial disclosures.

Although it is often taken for granted, the ability to initiate and maintain sleep throughout the night is elusive for many. About one-third of adults experience a troublesome episode of insomnia.¹ In most, it is transient, but in 10% to 15% (roughly 30 million people), the problem becomes self-perpetuating and chronic.² Chronic insomnia is one of the most prevalent conditions that family physicians (FPs) encounter, a function of it being so closely associated with comorbid conditions that FPs deal with every day, such as depression, chronic pain, and polypharmacy.^3,4

Insomnia can be vexing for a number of reasons. Because it is not acutely dangerous, patients may present it as an “add-on” concern at the end of an already lengthy visit. And because insomnia is often a symptom of multiple underlying physiologic and psychological factors, it requires the FP to engage in a thorough and time-consuming exploration of possible causes and comorbidities. Finally, standard treatment options have drawbacks: reports show that use of pharmacotherapy is troubling to prescribers primarily because of concerns about adverse effects and dependence;^5-7 the other major therapeutic avenue, cognitive behavioral therapy for insomnia (CBT-I), requires training and is time-consuming to deliver in the context of an office visit.^8,9

Despite these obstacles, successful evaluation and treatment of insomnia can be highly rewarding. Chronic insomnia is associated with great individual misery and negative consequences for long-term health. Specifically, it is associated with reduced quality of life and daytime functioning,¹⁰ depression,^11,12 hypertension,^13,14 increased workplace accidents and absenteeism,^15-17 and exacerbations of chronic pain.¹⁸ And while the evaluation and management of insomnia can be laborious, a systematic method can streamline the process.

Insomnia: Symptom or cause?

The International Classification of Sleep Disorders defines chronic insomnia as an inability to sleep sufficiently despite creating adequate opportunity. It occurs at least 3 nights per week for >3 months with perceived negative consequences during the day. Patients typically complain about symptoms including fatigue, diminished cog­nitive performance, and mood disturbance.¹⁹ Acute insomnia triggered by one or more biopsychosocial stresses is, by definition, self-limited and has different underlying mechanisms. As such, it will not be described in this review.

The chief risk factors are female gender, low socioeconomic status, and increasing age.²⁰ However, cohorts of healthy seniors show preserved good sleep; the increase in prevalence of insomnia in the elderly is likely linked more specifically to age-related accumulation of medical/mental health disorders and polypharmacy than aging per se.²¹

Research over the past 20 years has shown that comorbidities have a bidirectional relationship with insomnia, rather than a one-way cause and effect.

In the past, insomnia was viewed as a symptom, occurring secondarily to an underlying cause, usually an acute biopsychosocial stressor or depression. It was assumed that if the primary cause was effectively treated, then healthy sleep would return.

But research over the past 20 years has changed this paradigm in 2 ways. First, when comorbidities such as depression or chronic pain are present, they have a bidirectional relationship with insomnia rather than a one-way cause and effect. For example, instead of depression being a primary disorder from which insomnia can result, it is now recognized that insomnia can be present first and is a risk factor for new-onset depression. When depression and insomnia coexist, they may exacerbate each other in a bidirectional pattern.

Secondly, an estimated 15% of chronic insomnia sufferers have no targetable comorbidity; rather, they are unable to get sufficient sleep in large part because of a trait-like predisposition to fragile sleep, called hyperarousal brain physiology.²² These people used to be described as having “primary insomnia,” although the term has been dropped from the 5th edition of The Diagnostic and Statistical Manual of Mental Disorders (DSM).²³

Assess comorbidities, obtain sleep logs

The evaluation of the chronic form of insomnia should begin with a thorough medical his­tory to assess for comorbid conditions that can exacerbate disturbed sleep. These are generally grouped into medical disorders (TABLE 1²⁰), medications/substances (eg, antidepressants, stimulants, decongestants, narcotic analgesics, cardiovascular drugs, pulmonary agents, alcohol), and mental health disorders (especially depression and anxiety). It’s important to consider whether such comorbidities are contributing to the insomnia and optimize treatment that addresses them.

Take particular care to evaluate signs and symptoms of comorbid primary sleep disorders such as obstructive sleep apnea, restless legs syndrome (RLS), and circadian rhythm disorders since any of these can present with a complaint of insomnia. RLS, usually classified as a sleep disorder because of its circadian pattern (it is experienced more at night than during the day), is present to a troublesome degree in about 3% to 4% of all adults.²⁴ It is important to inquire about symptoms of RLS (urge to move legs in the night more than during the day; relieved with movement; worsened with inactivity) so as not to miss this treatable cause of insomnia.

The physical exam should focus on signs that suggest sleep-disordered breathing—obesity, large neck girth, hypertension, and crowded oropharynx—because people with sleep apnea often present with the complaint of frequent awakenings.

Sleep logs can present a powerful picture

In addition to a history and physical exam, physicians should ask their patients with chronic insomnia to complete sleep logs for 2 to 3 weeks.²⁰ A sleep log with midnight near the middle of the page is preferred by many because it places the typical sleeping hours in the middle of the page, showing relevant information in a way that can be grasped immediately (FIGURE 1). To save time, nurses can provide sleep logs to patients along with instructions about how to complete them.

Patient-completed sleep logs often illuminate obvious detrimental behaviors that reinforce insomnia (eg, spending excessive time in bed, having irregular bed/wake times, daytime napping that diminishes sleep drive in the evening). In addition, they sometimes reveal circadian rhythm abnormalities such as delayed sleep phase syndrome in which the patient attempts to sleep at a normal bedtime, but exhibits a marked delay in falling asleep/waking up compared to societal norms. Seeing such information graphically represented is often a powerful learning experience for both physician and patient.

Sleep studies aren't usually warranted

In its most recent (2008) clinical guideline on the evaluation and management of chronic insomnia, the American Academy of Sleep Medicine (AASM) stated that “routine testing in the sleep lab is not warranted for most cases of insomnia.” Instead, it is reserved for individuals in whom there is a suspicion of a comorbid sleep disorder. FPs should refer patients for formal sleep studies only if, in addition to the insomnia complaint, there is suspicion of:²⁰

• obstructive sleep apnea (based upon some combination of loud snoring, obesity, hypertension, and/or excessive daytime sleepiness),
• narcolepsy (based upon excessive daytime sleepiness without a readily identifiable cause), or
• arousals with the potential for self-injurious behavior (parasomnias).

Treatments: Sleep hygiene, CBT-I, and medication

Sleep hygiene, cognitive/behavioral techniques, and pharmacotherapy serve as the core of therapy for chronic insomnia.

Sleep hygiene: Common-sense strategies

Most FPs are familiar with sleep hygiene instructions; these are simple, common-sense behavioral techniques such as limiting caffeine and screen (television, computer) time at night, avoiding daytime naps, and maintaining regular bed- and out-of-bed times. (See “A sleep hygiene checklist.”) Although it is a logical starting point for behavioral modification, sleep hygiene has not been studied rigorously as a monotherapy for insomnia and, therefore, doesn’t have an evidence rating in terms of effectiveness.²⁰

CBT-I: Treatment of choice

CBT-I seeks to lower cognitive and somatic arousal. Taken together, cognitive and behavioral techniques are effective in 70% to 80% of people, whether they have primary insomnia or comorbidities.^25-27 Furthermore, the benefits are sustained with the passage of time.²⁷ CBT-I is regarded as the treatment of choice for chronic insomnia.²⁰

An experience of successful sleep initiation and maintenance is important psychologically: It renews patients' confidence in the ability to sleep.

When provided by a highly trained mental health professional, CBT-I usually takes the form of a series of 6 to 8 weekly appointments. Descriptions and manuals for CBT-I abound and online programs have also proliferated.^28,29 However, there is a shortage of highly trained providers, and most FPs do not feel proficient to engage fully in CBT-I.^8,9 Nevertheless, some behavioral elements of CBT-I, such as stimulus control and sleep restriction, can be utilized in the family medicine setting and may be effective for a significant subset of patients.

Stimulus control and sleep restriction. Two behavioral techniques for insomnia that can be applied in the family medicine setting are stimulus control and sleep restriction therapy.²⁰

With stimulus control, patients attempt to eliminate stimuli that weaken the psychological association between the bed and successful sleep, namely wakeful activities in bed such as watching television, reading, or even “tossing and turning.” Instead, they are instructed to use their bed only for sleep (and intimacy), to vacate it if awake and not clearly on the verge of sleep, and to avoid looking at a clock during the night. Patients are also advised to sleep only in their own bed and not in other places in their home.

Sleep restriction is predicated on the observation that many people with insomnia habitually spend too much time awake in bed, and this creates a conditioned arousal response to the bed. With sleep restriction, the patient is assigned a narrow window of “allowed time in bed,” usually a 6-hour interval of their choosing, and is instructed to adhere to this schedule for a period of 2 to 4 weeks. Many patients find that they fall asleep more rapidly and stay asleep longer after a few weeks. This experience of “successful” sleep initiation and maintenance is important psychologically; it renews their confidence in their ability to sleep, which is missing in most people with chronic insomnia.

If you use this approach with a patient, be sure to acknowledge that sleep restriction usually engenders some sleep deprivation in the first few weeks. But it is only a short-term intervention designed to change the expectation of nightly insomnia that is so ingrained in these patients. While they engage in sleep restriction, patients should keep sleep logs to track their “sleep efficiency” (ie, estimated time asleep vs time in bed). Once good sleep efficiency (>85%) is achieved, they may gradually lengthen their allowed time in bed by 15 minutes each week until they are obtaining 7 to 9 hours of sleep per night. (See “Breaking the cycle of insomnia by employing sleep restriction.”)

Cognitive therapy. Cognitive therapies for insomnia are usually provided by psychologists with special training. Three specific techniques that have evidence ratings* from the AASM are:²⁰

1. Relaxation training, including progressive muscle relaxation, guided imagery, and abdominal breathing to lower somatic and cognitive arousal states that interfere with sleep (strength of recommendation [SOR]: A).
2. Biofeedback therapy trains patients to control some physiologic variable through visual or auditory feedback. The objective is to reduce somatic arousal (SOR: B).
3. Paradoxical intention in which the patient is trained to confront the fear of staying awake and its potential effects. The objective is to eliminate a patient’s anxiety about sleep performance (SOR: B).

Pharmacotherapy: Overused? Addictive?

For patients who continue to struggle with insomnia despite attempting CBT-I, or for those who prefer a different approach, pharmacotherapy is a reasonable therapeutic option. While hypnotic medications are no guarantee of success, they sometimes provide meaningful benefit when supplied to a patient who has successfully established good cognitive and behavioral techniques, but is still struggling with insomnia.

Use of hypnotic medications has increased dramatically in recent years. Prescriptions for sleep medications approached 60 million in 2008, up 54% from 2004, with sales topping $2 billion.^30,31 A National Health and Nutrition Examination Survey looking at the period between 2005 and 2010 found that about 4% of adults ages 20 and older used prescription sleep aids in the past month.³²

Meta-analyses of pharmacotherapy for chronic insomnia show small to moderate effect sizes for sleep variables such as latency to sleep onset, total sleep time, and wake time after sleep onset.^33,34 Treatment of chronic insomnia with hypnotic medications is of comparable effectiveness to CBT-I in the early phase, but the benefits of CBT-I are more enduring.²⁷

A controversial approach. The appropriateness of hypnotic medications for chronic insomnia is controversial. While their use by health care professionals has been increasing, some authors have raised concerns about sleeping pills, citing a lack of effectiveness and possible adverse effects such as falls, driving impairment, and the potential for addiction, tolerance, and dependence.^33,35 The Beers Criteria of the American Geriatric Society recommends against the use of benzodiazepines in the elderly due to the risks of falls, cognitive impairment, and motor vehicle accidents and advises against the use of benzodiazepine agonists (such as zolpidem) for >90 days.³⁶

Two behavioral techniques for insomnia that can be easily applied in the family medicine setting are stimulus control and sleep restriction therapy.

Despite these concerns, the potential benefits of hypnotic medications for chronic insomnia should not be dismissed. The common strategy of simply addressing comorbidities and advising good sleep hygiene is insufficient for many patients. And some patients prefer the ease of using a hypnotic agent to the commitment required by CBT-I. Several reports suggest that the risk of hypnotic medication misuse in people with no history of substance abuse is overestimated.^37,38 And a panel of insomnia experts convened for the New Clinical Drug Evaluation Unit symposium in 2001 concluded, “Patients with chronic insomnia tend to exhibit therapy-seeking behavior, not drug-seeking behavior.”³⁹

Which hypnotic agent to choose?

US Food and Drug Administration (FDA)-approved hypnotic medications fall into 5 families (TABLE 2⁴⁰): benzodiazepines (BDZs), benzodiazepine agonists (BDZAs, sometimes called “Z drugs”), melatonin agonists (eg, ramelteon), tricyclic antidepressants (eg, low-dose doxepin), and orexin antagonists (eg, suvorexant). BDZs, BDZAs, and melatonin agonists potentiate sleep-promoting systems, while orexin antagonists and antihistaminergics suppress wake-promoting systems.

"Patients with chronic insomnia tend to exhibit therapy-seeking behavior, not drug-seeking behavior."

Studies of physician prescribing patterns show that among prescription medications for insomnia, zolpidem is the most popular, followed by trazodone (off-label use), other benzodiazepines, quetiapine (off-label use), and doxepin.⁴¹ Overall, over-the-counter melatonin may be more widely used than any of the prescription choices.⁴²

One useful basis for selection of an agent is whether the patient complains of difficulty with sleep initiation at the beginning of the night vs sleep maintenance, or both. For sleep initiation complaints, short-acting/sleep-promoting agents are preferred. For sleep maintenance complaints, longer-acting/wake-inhibiting medications that work at the end of the sleep phase may be necessary.

The AASM has recently concluded an exhaustive review of the literature regarding hypnotic medications for chronic insomnia.⁴³ The authors acknowledge important methodologic limitations, most notably a paucity of data on effectiveness and adverse effects, along with industry sponsorship of most studies and publication bias. Nevertheless, their conclusions favor the use of FDA-approved agents to off-label use of trazodone or over-the-counter use of melatonin or diphenhydramine. To summarize the AASM guidelines:³⁸

1. Medications recommended for sleep onset insomnia include: eszopiclone, ramelteon, temazepam, triazolam, zaleplon, and zolpidem.
2. Medications recommended for treating sleep maintenance insomnia include: doxepin, eszopiclone, suvorexant, zolpidem, and temazepam.
3. Medications not recommended for treating either sleep initiation or sleep maintenance insomnia include: diphenhydramine, melatonin, tiagabine, trazodone, tryptophan, and valerian.

These recommendations are similar to a review of hypnotics published by The Medical Letter in 2015.⁴⁰
 

Trazodone, an antidepressant medication with sedating properties, is not FDA-approved for the treatment of insomnia, yet ranks second to zolpidem in the number of prescriptions written for insomnia. Its popularity may be due to a perception of safety implied by its unscheduled FDA status and the lack of restrictions on prescribing duration. However, several reviews point out that its evidence base is weak.^44,45 There is only one placebo-controlled study involving trazodone use for "primary insomnia" (other studies have been in people with comorbid depression) and it showed insignificant improvements in sleep parameters and less effectiveness compared to zolpidem.⁴⁶

Trazadone, an antidepressant with sedating properties, is not FDA-approved for the treatment of insomnia, yet ranks second to zolpidem in the number of prescriptions written for insomnia.

Trazodone’s mechanisms of action are thought to be serotonin reuptake inhibition and alpha blockade, which might explain adverse effects such as orthostatic hypotension and psychomotor impairment. The frequency of such adverse effects is difficult to estimate since most studies of trazodone have used higher doses than are commonly used for insomnia in order to address comorbid depression. However, some experts have cautioned against its use—especially in the elderly.

The AASM guidelines recommend against use of trazodone. Others assert that it is probably best reserved for people in whom the complaint of insomnia is linked to comorbid depression.^43,44 

Is long-term use ever appropriate? There are no published guidelines about dosing strategies for hypnotics and whether nightly or intermittent use is preferred. All FDA-approved hypnotic agents are for short-term use, but this designation stems from a lack of long-term studies demonstrating continuing efficacy rather than actual proof of loss of effect. Although tolerance to over-the-counter sleep aids does occur, it has not been demonstrated to occur with FDA-approved agents. Studies of eszopiclone and zolpidem indicate continuing effectiveness as hypnotics with nightly use over a time-frame of several months to one year.^47,48

Regarding the thorny question of long-term use of hypnotics for chronic insomnia, the AASM concluded that long-term use should be reserved for “individuals in whom CBT-I is inaccessible or ineffective, who have been appropriately screened for contraindications to such treatment, who maintain long-term gains with medication, and who are followed regularly.”⁴³

CORRESPONDENCE
Adam J. Sorscher, MD, Dartmouth-Hitchcock Medical Center, 18 Old Etna Road, Lebanon, NH 03766; [email protected].

Although it is often taken for granted, the ability to initiate and maintain sleep throughout the night is elusive for many. About one-third of adults experience a troublesome episode of insomnia.¹ In most, it is transient, but in 10% to 15% (roughly 30 million people), the problem becomes self-perpetuating and chronic.² Chronic insomnia is one of the most prevalent conditions that family physicians (FPs) encounter, a function of it being so closely associated with comorbid conditions that FPs deal with every day, such as depression, chronic pain, and polypharmacy.^3,4

Insomnia can be vexing for a number of reasons. Because it is not acutely dangerous, patients may present it as an “add-on” concern at the end of an already lengthy visit. And because insomnia is often a symptom of multiple underlying physiologic and psychological factors, it requires the FP to engage in a thorough and time-consuming exploration of possible causes and comorbidities. Finally, standard treatment options have drawbacks: reports show that use of pharmacotherapy is troubling to prescribers primarily because of concerns about adverse effects and dependence;^5-7 the other major therapeutic avenue, cognitive behavioral therapy for insomnia (CBT-I), requires training and is time-consuming to deliver in the context of an office visit.^8,9

Despite these obstacles, successful evaluation and treatment of insomnia can be highly rewarding. Chronic insomnia is associated with great individual misery and negative consequences for long-term health. Specifically, it is associated with reduced quality of life and daytime functioning,¹⁰ depression,^11,12 hypertension,^13,14 increased workplace accidents and absenteeism,^15-17 and exacerbations of chronic pain.¹⁸ And while the evaluation and management of insomnia can be laborious, a systematic method can streamline the process.

Insomnia: Symptom or cause?

The International Classification of Sleep Disorders defines chronic insomnia as an inability to sleep sufficiently despite creating adequate opportunity. It occurs at least 3 nights per week for >3 months with perceived negative consequences during the day. Patients typically complain about symptoms including fatigue, diminished cog­nitive performance, and mood disturbance.¹⁹ Acute insomnia triggered by one or more biopsychosocial stresses is, by definition, self-limited and has different underlying mechanisms. As such, it will not be described in this review.

The chief risk factors are female gender, low socioeconomic status, and increasing age.²⁰ However, cohorts of healthy seniors show preserved good sleep; the increase in prevalence of insomnia in the elderly is likely linked more specifically to age-related accumulation of medical/mental health disorders and polypharmacy than aging per se.²¹

Research over the past 20 years has shown that comorbidities have a bidirectional relationship with insomnia, rather than a one-way cause and effect.

In the past, insomnia was viewed as a symptom, occurring secondarily to an underlying cause, usually an acute biopsychosocial stressor or depression. It was assumed that if the primary cause was effectively treated, then healthy sleep would return.

But research over the past 20 years has changed this paradigm in 2 ways. First, when comorbidities such as depression or chronic pain are present, they have a bidirectional relationship with insomnia rather than a one-way cause and effect. For example, instead of depression being a primary disorder from which insomnia can result, it is now recognized that insomnia can be present first and is a risk factor for new-onset depression. When depression and insomnia coexist, they may exacerbate each other in a bidirectional pattern.

Secondly, an estimated 15% of chronic insomnia sufferers have no targetable comorbidity; rather, they are unable to get sufficient sleep in large part because of a trait-like predisposition to fragile sleep, called hyperarousal brain physiology.²² These people used to be described as having “primary insomnia,” although the term has been dropped from the 5th edition of The Diagnostic and Statistical Manual of Mental Disorders (DSM).²³

Assess comorbidities, obtain sleep logs

The evaluation of the chronic form of insomnia should begin with a thorough medical his­tory to assess for comorbid conditions that can exacerbate disturbed sleep. These are generally grouped into medical disorders (TABLE 1²⁰), medications/substances (eg, antidepressants, stimulants, decongestants, narcotic analgesics, cardiovascular drugs, pulmonary agents, alcohol), and mental health disorders (especially depression and anxiety). It’s important to consider whether such comorbidities are contributing to the insomnia and optimize treatment that addresses them.

Take particular care to evaluate signs and symptoms of comorbid primary sleep disorders such as obstructive sleep apnea, restless legs syndrome (RLS), and circadian rhythm disorders since any of these can present with a complaint of insomnia. RLS, usually classified as a sleep disorder because of its circadian pattern (it is experienced more at night than during the day), is present to a troublesome degree in about 3% to 4% of all adults.²⁴ It is important to inquire about symptoms of RLS (urge to move legs in the night more than during the day; relieved with movement; worsened with inactivity) so as not to miss this treatable cause of insomnia.

The physical exam should focus on signs that suggest sleep-disordered breathing—obesity, large neck girth, hypertension, and crowded oropharynx—because people with sleep apnea often present with the complaint of frequent awakenings.

Sleep logs can present a powerful picture

In addition to a history and physical exam, physicians should ask their patients with chronic insomnia to complete sleep logs for 2 to 3 weeks.²⁰ A sleep log with midnight near the middle of the page is preferred by many because it places the typical sleeping hours in the middle of the page, showing relevant information in a way that can be grasped immediately (FIGURE 1). To save time, nurses can provide sleep logs to patients along with instructions about how to complete them.

Patient-completed sleep logs often illuminate obvious detrimental behaviors that reinforce insomnia (eg, spending excessive time in bed, having irregular bed/wake times, daytime napping that diminishes sleep drive in the evening). In addition, they sometimes reveal circadian rhythm abnormalities such as delayed sleep phase syndrome in which the patient attempts to sleep at a normal bedtime, but exhibits a marked delay in falling asleep/waking up compared to societal norms. Seeing such information graphically represented is often a powerful learning experience for both physician and patient.

Sleep studies aren't usually warranted

In its most recent (2008) clinical guideline on the evaluation and management of chronic insomnia, the American Academy of Sleep Medicine (AASM) stated that “routine testing in the sleep lab is not warranted for most cases of insomnia.” Instead, it is reserved for individuals in whom there is a suspicion of a comorbid sleep disorder. FPs should refer patients for formal sleep studies only if, in addition to the insomnia complaint, there is suspicion of:²⁰

• obstructive sleep apnea (based upon some combination of loud snoring, obesity, hypertension, and/or excessive daytime sleepiness),
• narcolepsy (based upon excessive daytime sleepiness without a readily identifiable cause), or
• arousals with the potential for self-injurious behavior (parasomnias).

Treatments: Sleep hygiene, CBT-I, and medication

Sleep hygiene, cognitive/behavioral techniques, and pharmacotherapy serve as the core of therapy for chronic insomnia.

Sleep hygiene: Common-sense strategies

Most FPs are familiar with sleep hygiene instructions; these are simple, common-sense behavioral techniques such as limiting caffeine and screen (television, computer) time at night, avoiding daytime naps, and maintaining regular bed- and out-of-bed times. (See “A sleep hygiene checklist.”) Although it is a logical starting point for behavioral modification, sleep hygiene has not been studied rigorously as a monotherapy for insomnia and, therefore, doesn’t have an evidence rating in terms of effectiveness.²⁰

CBT-I: Treatment of choice

CBT-I seeks to lower cognitive and somatic arousal. Taken together, cognitive and behavioral techniques are effective in 70% to 80% of people, whether they have primary insomnia or comorbidities.^25-27 Furthermore, the benefits are sustained with the passage of time.²⁷ CBT-I is regarded as the treatment of choice for chronic insomnia.²⁰

An experience of successful sleep initiation and maintenance is important psychologically: It renews patients' confidence in the ability to sleep.

When provided by a highly trained mental health professional, CBT-I usually takes the form of a series of 6 to 8 weekly appointments. Descriptions and manuals for CBT-I abound and online programs have also proliferated.^28,29 However, there is a shortage of highly trained providers, and most FPs do not feel proficient to engage fully in CBT-I.^8,9 Nevertheless, some behavioral elements of CBT-I, such as stimulus control and sleep restriction, can be utilized in the family medicine setting and may be effective for a significant subset of patients.

Stimulus control and sleep restriction. Two behavioral techniques for insomnia that can be applied in the family medicine setting are stimulus control and sleep restriction therapy.²⁰

With stimulus control, patients attempt to eliminate stimuli that weaken the psychological association between the bed and successful sleep, namely wakeful activities in bed such as watching television, reading, or even “tossing and turning.” Instead, they are instructed to use their bed only for sleep (and intimacy), to vacate it if awake and not clearly on the verge of sleep, and to avoid looking at a clock during the night. Patients are also advised to sleep only in their own bed and not in other places in their home.

Sleep restriction is predicated on the observation that many people with insomnia habitually spend too much time awake in bed, and this creates a conditioned arousal response to the bed. With sleep restriction, the patient is assigned a narrow window of “allowed time in bed,” usually a 6-hour interval of their choosing, and is instructed to adhere to this schedule for a period of 2 to 4 weeks. Many patients find that they fall asleep more rapidly and stay asleep longer after a few weeks. This experience of “successful” sleep initiation and maintenance is important psychologically; it renews their confidence in their ability to sleep, which is missing in most people with chronic insomnia.

If you use this approach with a patient, be sure to acknowledge that sleep restriction usually engenders some sleep deprivation in the first few weeks. But it is only a short-term intervention designed to change the expectation of nightly insomnia that is so ingrained in these patients. While they engage in sleep restriction, patients should keep sleep logs to track their “sleep efficiency” (ie, estimated time asleep vs time in bed). Once good sleep efficiency (>85%) is achieved, they may gradually lengthen their allowed time in bed by 15 minutes each week until they are obtaining 7 to 9 hours of sleep per night. (See “Breaking the cycle of insomnia by employing sleep restriction.”)

Cognitive therapy. Cognitive therapies for insomnia are usually provided by psychologists with special training. Three specific techniques that have evidence ratings* from the AASM are:²⁰

1. Relaxation training, including progressive muscle relaxation, guided imagery, and abdominal breathing to lower somatic and cognitive arousal states that interfere with sleep (strength of recommendation [SOR]: A).
2. Biofeedback therapy trains patients to control some physiologic variable through visual or auditory feedback. The objective is to reduce somatic arousal (SOR: B).
3. Paradoxical intention in which the patient is trained to confront the fear of staying awake and its potential effects. The objective is to eliminate a patient’s anxiety about sleep performance (SOR: B).

Pharmacotherapy: Overused? Addictive?

For patients who continue to struggle with insomnia despite attempting CBT-I, or for those who prefer a different approach, pharmacotherapy is a reasonable therapeutic option. While hypnotic medications are no guarantee of success, they sometimes provide meaningful benefit when supplied to a patient who has successfully established good cognitive and behavioral techniques, but is still struggling with insomnia.

Use of hypnotic medications has increased dramatically in recent years. Prescriptions for sleep medications approached 60 million in 2008, up 54% from 2004, with sales topping $2 billion.^30,31 A National Health and Nutrition Examination Survey looking at the period between 2005 and 2010 found that about 4% of adults ages 20 and older used prescription sleep aids in the past month.³²

Meta-analyses of pharmacotherapy for chronic insomnia show small to moderate effect sizes for sleep variables such as latency to sleep onset, total sleep time, and wake time after sleep onset.^33,34 Treatment of chronic insomnia with hypnotic medications is of comparable effectiveness to CBT-I in the early phase, but the benefits of CBT-I are more enduring.²⁷

A controversial approach. The appropriateness of hypnotic medications for chronic insomnia is controversial. While their use by health care professionals has been increasing, some authors have raised concerns about sleeping pills, citing a lack of effectiveness and possible adverse effects such as falls, driving impairment, and the potential for addiction, tolerance, and dependence.^33,35 The Beers Criteria of the American Geriatric Society recommends against the use of benzodiazepines in the elderly due to the risks of falls, cognitive impairment, and motor vehicle accidents and advises against the use of benzodiazepine agonists (such as zolpidem) for >90 days.³⁶

Two behavioral techniques for insomnia that can be easily applied in the family medicine setting are stimulus control and sleep restriction therapy.

Despite these concerns, the potential benefits of hypnotic medications for chronic insomnia should not be dismissed. The common strategy of simply addressing comorbidities and advising good sleep hygiene is insufficient for many patients. And some patients prefer the ease of using a hypnotic agent to the commitment required by CBT-I. Several reports suggest that the risk of hypnotic medication misuse in people with no history of substance abuse is overestimated.^37,38 And a panel of insomnia experts convened for the New Clinical Drug Evaluation Unit symposium in 2001 concluded, “Patients with chronic insomnia tend to exhibit therapy-seeking behavior, not drug-seeking behavior.”³⁹

Which hypnotic agent to choose?

US Food and Drug Administration (FDA)-approved hypnotic medications fall into 5 families (TABLE 2⁴⁰): benzodiazepines (BDZs), benzodiazepine agonists (BDZAs, sometimes called “Z drugs”), melatonin agonists (eg, ramelteon), tricyclic antidepressants (eg, low-dose doxepin), and orexin antagonists (eg, suvorexant). BDZs, BDZAs, and melatonin agonists potentiate sleep-promoting systems, while orexin antagonists and antihistaminergics suppress wake-promoting systems.

"Patients with chronic insomnia tend to exhibit therapy-seeking behavior, not drug-seeking behavior."

Studies of physician prescribing patterns show that among prescription medications for insomnia, zolpidem is the most popular, followed by trazodone (off-label use), other benzodiazepines, quetiapine (off-label use), and doxepin.⁴¹ Overall, over-the-counter melatonin may be more widely used than any of the prescription choices.⁴²

One useful basis for selection of an agent is whether the patient complains of difficulty with sleep initiation at the beginning of the night vs sleep maintenance, or both. For sleep initiation complaints, short-acting/sleep-promoting agents are preferred. For sleep maintenance complaints, longer-acting/wake-inhibiting medications that work at the end of the sleep phase may be necessary.

The AASM has recently concluded an exhaustive review of the literature regarding hypnotic medications for chronic insomnia.⁴³ The authors acknowledge important methodologic limitations, most notably a paucity of data on effectiveness and adverse effects, along with industry sponsorship of most studies and publication bias. Nevertheless, their conclusions favor the use of FDA-approved agents to off-label use of trazodone or over-the-counter use of melatonin or diphenhydramine. To summarize the AASM guidelines:³⁸

1. Medications recommended for sleep onset insomnia include: eszopiclone, ramelteon, temazepam, triazolam, zaleplon, and zolpidem.
2. Medications recommended for treating sleep maintenance insomnia include: doxepin, eszopiclone, suvorexant, zolpidem, and temazepam.
3. Medications not recommended for treating either sleep initiation or sleep maintenance insomnia include: diphenhydramine, melatonin, tiagabine, trazodone, tryptophan, and valerian.

These recommendations are similar to a review of hypnotics published by The Medical Letter in 2015.⁴⁰
 

Trazodone, an antidepressant medication with sedating properties, is not FDA-approved for the treatment of insomnia, yet ranks second to zolpidem in the number of prescriptions written for insomnia. Its popularity may be due to a perception of safety implied by its unscheduled FDA status and the lack of restrictions on prescribing duration. However, several reviews point out that its evidence base is weak.^44,45 There is only one placebo-controlled study involving trazodone use for "primary insomnia" (other studies have been in people with comorbid depression) and it showed insignificant improvements in sleep parameters and less effectiveness compared to zolpidem.⁴⁶

Trazadone, an antidepressant with sedating properties, is not FDA-approved for the treatment of insomnia, yet ranks second to zolpidem in the number of prescriptions written for insomnia.

Trazodone’s mechanisms of action are thought to be serotonin reuptake inhibition and alpha blockade, which might explain adverse effects such as orthostatic hypotension and psychomotor impairment. The frequency of such adverse effects is difficult to estimate since most studies of trazodone have used higher doses than are commonly used for insomnia in order to address comorbid depression. However, some experts have cautioned against its use—especially in the elderly.

The AASM guidelines recommend against use of trazodone. Others assert that it is probably best reserved for people in whom the complaint of insomnia is linked to comorbid depression.^43,44 

Is long-term use ever appropriate? There are no published guidelines about dosing strategies for hypnotics and whether nightly or intermittent use is preferred. All FDA-approved hypnotic agents are for short-term use, but this designation stems from a lack of long-term studies demonstrating continuing efficacy rather than actual proof of loss of effect. Although tolerance to over-the-counter sleep aids does occur, it has not been demonstrated to occur with FDA-approved agents. Studies of eszopiclone and zolpidem indicate continuing effectiveness as hypnotics with nightly use over a time-frame of several months to one year.^47,48

Regarding the thorny question of long-term use of hypnotics for chronic insomnia, the AASM concluded that long-term use should be reserved for “individuals in whom CBT-I is inaccessible or ineffective, who have been appropriately screened for contraindications to such treatment, who maintain long-term gains with medication, and who are followed regularly.”⁴³

CORRESPONDENCE
Adam J. Sorscher, MD, Dartmouth-Hitchcock Medical Center, 18 Old Etna Road, Lebanon, NH 03766; [email protected].

Although it is often taken for granted, the ability to initiate and maintain sleep throughout the night is elusive for many. About one-third of adults experience a troublesome episode of insomnia.¹ In most, it is transient, but in 10% to 15% (roughly 30 million people), the problem becomes self-perpetuating and chronic.² Chronic insomnia is one of the most prevalent conditions that family physicians (FPs) encounter, a function of it being so closely associated with comorbid conditions that FPs deal with every day, such as depression, chronic pain, and polypharmacy.^3,4

Insomnia can be vexing for a number of reasons. Because it is not acutely dangerous, patients may present it as an “add-on” concern at the end of an already lengthy visit. And because insomnia is often a symptom of multiple underlying physiologic and psychological factors, it requires the FP to engage in a thorough and time-consuming exploration of possible causes and comorbidities. Finally, standard treatment options have drawbacks: reports show that use of pharmacotherapy is troubling to prescribers primarily because of concerns about adverse effects and dependence;^5-7 the other major therapeutic avenue, cognitive behavioral therapy for insomnia (CBT-I), requires training and is time-consuming to deliver in the context of an office visit.^8,9

Despite these obstacles, successful evaluation and treatment of insomnia can be highly rewarding. Chronic insomnia is associated with great individual misery and negative consequences for long-term health. Specifically, it is associated with reduced quality of life and daytime functioning,¹⁰ depression,^11,12 hypertension,^13,14 increased workplace accidents and absenteeism,^15-17 and exacerbations of chronic pain.¹⁸ And while the evaluation and management of insomnia can be laborious, a systematic method can streamline the process.

Insomnia: Symptom or cause?

The International Classification of Sleep Disorders defines chronic insomnia as an inability to sleep sufficiently despite creating adequate opportunity. It occurs at least 3 nights per week for >3 months with perceived negative consequences during the day. Patients typically complain about symptoms including fatigue, diminished cog­nitive performance, and mood disturbance.¹⁹ Acute insomnia triggered by one or more biopsychosocial stresses is, by definition, self-limited and has different underlying mechanisms. As such, it will not be described in this review.

The chief risk factors are female gender, low socioeconomic status, and increasing age.²⁰ However, cohorts of healthy seniors show preserved good sleep; the increase in prevalence of insomnia in the elderly is likely linked more specifically to age-related accumulation of medical/mental health disorders and polypharmacy than aging per se.²¹

Research over the past 20 years has shown that comorbidities have a bidirectional relationship with insomnia, rather than a one-way cause and effect.

In the past, insomnia was viewed as a symptom, occurring secondarily to an underlying cause, usually an acute biopsychosocial stressor or depression. It was assumed that if the primary cause was effectively treated, then healthy sleep would return.

But research over the past 20 years has changed this paradigm in 2 ways. First, when comorbidities such as depression or chronic pain are present, they have a bidirectional relationship with insomnia rather than a one-way cause and effect. For example, instead of depression being a primary disorder from which insomnia can result, it is now recognized that insomnia can be present first and is a risk factor for new-onset depression. When depression and insomnia coexist, they may exacerbate each other in a bidirectional pattern.

Secondly, an estimated 15% of chronic insomnia sufferers have no targetable comorbidity; rather, they are unable to get sufficient sleep in large part because of a trait-like predisposition to fragile sleep, called hyperarousal brain physiology.²² These people used to be described as having “primary insomnia,” although the term has been dropped from the 5th edition of The Diagnostic and Statistical Manual of Mental Disorders (DSM).²³

Assess comorbidities, obtain sleep logs

The evaluation of the chronic form of insomnia should begin with a thorough medical his­tory to assess for comorbid conditions that can exacerbate disturbed sleep. These are generally grouped into medical disorders (TABLE 1²⁰), medications/substances (eg, antidepressants, stimulants, decongestants, narcotic analgesics, cardiovascular drugs, pulmonary agents, alcohol), and mental health disorders (especially depression and anxiety). It’s important to consider whether such comorbidities are contributing to the insomnia and optimize treatment that addresses them.

Take particular care to evaluate signs and symptoms of comorbid primary sleep disorders such as obstructive sleep apnea, restless legs syndrome (RLS), and circadian rhythm disorders since any of these can present with a complaint of insomnia. RLS, usually classified as a sleep disorder because of its circadian pattern (it is experienced more at night than during the day), is present to a troublesome degree in about 3% to 4% of all adults.²⁴ It is important to inquire about symptoms of RLS (urge to move legs in the night more than during the day; relieved with movement; worsened with inactivity) so as not to miss this treatable cause of insomnia.

The physical exam should focus on signs that suggest sleep-disordered breathing—obesity, large neck girth, hypertension, and crowded oropharynx—because people with sleep apnea often present with the complaint of frequent awakenings.

Sleep logs can present a powerful picture

In addition to a history and physical exam, physicians should ask their patients with chronic insomnia to complete sleep logs for 2 to 3 weeks.²⁰ A sleep log with midnight near the middle of the page is preferred by many because it places the typical sleeping hours in the middle of the page, showing relevant information in a way that can be grasped immediately (FIGURE 1). To save time, nurses can provide sleep logs to patients along with instructions about how to complete them.

Patient-completed sleep logs often illuminate obvious detrimental behaviors that reinforce insomnia (eg, spending excessive time in bed, having irregular bed/wake times, daytime napping that diminishes sleep drive in the evening). In addition, they sometimes reveal circadian rhythm abnormalities such as delayed sleep phase syndrome in which the patient attempts to sleep at a normal bedtime, but exhibits a marked delay in falling asleep/waking up compared to societal norms. Seeing such information graphically represented is often a powerful learning experience for both physician and patient.

Sleep studies aren't usually warranted

In its most recent (2008) clinical guideline on the evaluation and management of chronic insomnia, the American Academy of Sleep Medicine (AASM) stated that “routine testing in the sleep lab is not warranted for most cases of insomnia.” Instead, it is reserved for individuals in whom there is a suspicion of a comorbid sleep disorder. FPs should refer patients for formal sleep studies only if, in addition to the insomnia complaint, there is suspicion of:²⁰

• obstructive sleep apnea (based upon some combination of loud snoring, obesity, hypertension, and/or excessive daytime sleepiness),
• narcolepsy (based upon excessive daytime sleepiness without a readily identifiable cause), or
• arousals with the potential for self-injurious behavior (parasomnias).

Treatments: Sleep hygiene, CBT-I, and medication

Sleep hygiene, cognitive/behavioral techniques, and pharmacotherapy serve as the core of therapy for chronic insomnia.

Sleep hygiene: Common-sense strategies

Most FPs are familiar with sleep hygiene instructions; these are simple, common-sense behavioral techniques such as limiting caffeine and screen (television, computer) time at night, avoiding daytime naps, and maintaining regular bed- and out-of-bed times. (See “A sleep hygiene checklist.”) Although it is a logical starting point for behavioral modification, sleep hygiene has not been studied rigorously as a monotherapy for insomnia and, therefore, doesn’t have an evidence rating in terms of effectiveness.²⁰

CBT-I: Treatment of choice

CBT-I seeks to lower cognitive and somatic arousal. Taken together, cognitive and behavioral techniques are effective in 70% to 80% of people, whether they have primary insomnia or comorbidities.^25-27 Furthermore, the benefits are sustained with the passage of time.²⁷ CBT-I is regarded as the treatment of choice for chronic insomnia.²⁰

An experience of successful sleep initiation and maintenance is important psychologically: It renews patients' confidence in the ability to sleep.

When provided by a highly trained mental health professional, CBT-I usually takes the form of a series of 6 to 8 weekly appointments. Descriptions and manuals for CBT-I abound and online programs have also proliferated.^28,29 However, there is a shortage of highly trained providers, and most FPs do not feel proficient to engage fully in CBT-I.^8,9 Nevertheless, some behavioral elements of CBT-I, such as stimulus control and sleep restriction, can be utilized in the family medicine setting and may be effective for a significant subset of patients.

Stimulus control and sleep restriction. Two behavioral techniques for insomnia that can be applied in the family medicine setting are stimulus control and sleep restriction therapy.²⁰

With stimulus control, patients attempt to eliminate stimuli that weaken the psychological association between the bed and successful sleep, namely wakeful activities in bed such as watching television, reading, or even “tossing and turning.” Instead, they are instructed to use their bed only for sleep (and intimacy), to vacate it if awake and not clearly on the verge of sleep, and to avoid looking at a clock during the night. Patients are also advised to sleep only in their own bed and not in other places in their home.

Sleep restriction is predicated on the observation that many people with insomnia habitually spend too much time awake in bed, and this creates a conditioned arousal response to the bed. With sleep restriction, the patient is assigned a narrow window of “allowed time in bed,” usually a 6-hour interval of their choosing, and is instructed to adhere to this schedule for a period of 2 to 4 weeks. Many patients find that they fall asleep more rapidly and stay asleep longer after a few weeks. This experience of “successful” sleep initiation and maintenance is important psychologically; it renews their confidence in their ability to sleep, which is missing in most people with chronic insomnia.

If you use this approach with a patient, be sure to acknowledge that sleep restriction usually engenders some sleep deprivation in the first few weeks. But it is only a short-term intervention designed to change the expectation of nightly insomnia that is so ingrained in these patients. While they engage in sleep restriction, patients should keep sleep logs to track their “sleep efficiency” (ie, estimated time asleep vs time in bed). Once good sleep efficiency (>85%) is achieved, they may gradually lengthen their allowed time in bed by 15 minutes each week until they are obtaining 7 to 9 hours of sleep per night. (See “Breaking the cycle of insomnia by employing sleep restriction.”)

Cognitive therapy. Cognitive therapies for insomnia are usually provided by psychologists with special training. Three specific techniques that have evidence ratings* from the AASM are:²⁰

1. Relaxation training, including progressive muscle relaxation, guided imagery, and abdominal breathing to lower somatic and cognitive arousal states that interfere with sleep (strength of recommendation [SOR]: A).
2. Biofeedback therapy trains patients to control some physiologic variable through visual or auditory feedback. The objective is to reduce somatic arousal (SOR: B).
3. Paradoxical intention in which the patient is trained to confront the fear of staying awake and its potential effects. The objective is to eliminate a patient’s anxiety about sleep performance (SOR: B).

Pharmacotherapy: Overused? Addictive?

For patients who continue to struggle with insomnia despite attempting CBT-I, or for those who prefer a different approach, pharmacotherapy is a reasonable therapeutic option. While hypnotic medications are no guarantee of success, they sometimes provide meaningful benefit when supplied to a patient who has successfully established good cognitive and behavioral techniques, but is still struggling with insomnia.

Use of hypnotic medications has increased dramatically in recent years. Prescriptions for sleep medications approached 60 million in 2008, up 54% from 2004, with sales topping $2 billion.^30,31 A National Health and Nutrition Examination Survey looking at the period between 2005 and 2010 found that about 4% of adults ages 20 and older used prescription sleep aids in the past month.³²

Meta-analyses of pharmacotherapy for chronic insomnia show small to moderate effect sizes for sleep variables such as latency to sleep onset, total sleep time, and wake time after sleep onset.^33,34 Treatment of chronic insomnia with hypnotic medications is of comparable effectiveness to CBT-I in the early phase, but the benefits of CBT-I are more enduring.²⁷

A controversial approach. The appropriateness of hypnotic medications for chronic insomnia is controversial. While their use by health care professionals has been increasing, some authors have raised concerns about sleeping pills, citing a lack of effectiveness and possible adverse effects such as falls, driving impairment, and the potential for addiction, tolerance, and dependence.^33,35 The Beers Criteria of the American Geriatric Society recommends against the use of benzodiazepines in the elderly due to the risks of falls, cognitive impairment, and motor vehicle accidents and advises against the use of benzodiazepine agonists (such as zolpidem) for >90 days.³⁶

Two behavioral techniques for insomnia that can be easily applied in the family medicine setting are stimulus control and sleep restriction therapy.

Despite these concerns, the potential benefits of hypnotic medications for chronic insomnia should not be dismissed. The common strategy of simply addressing comorbidities and advising good sleep hygiene is insufficient for many patients. And some patients prefer the ease of using a hypnotic agent to the commitment required by CBT-I. Several reports suggest that the risk of hypnotic medication misuse in people with no history of substance abuse is overestimated.^37,38 And a panel of insomnia experts convened for the New Clinical Drug Evaluation Unit symposium in 2001 concluded, “Patients with chronic insomnia tend to exhibit therapy-seeking behavior, not drug-seeking behavior.”³⁹

Which hypnotic agent to choose?

US Food and Drug Administration (FDA)-approved hypnotic medications fall into 5 families (TABLE 2⁴⁰): benzodiazepines (BDZs), benzodiazepine agonists (BDZAs, sometimes called “Z drugs”), melatonin agonists (eg, ramelteon), tricyclic antidepressants (eg, low-dose doxepin), and orexin antagonists (eg, suvorexant). BDZs, BDZAs, and melatonin agonists potentiate sleep-promoting systems, while orexin antagonists and antihistaminergics suppress wake-promoting systems.

"Patients with chronic insomnia tend to exhibit therapy-seeking behavior, not drug-seeking behavior."

Studies of physician prescribing patterns show that among prescription medications for insomnia, zolpidem is the most popular, followed by trazodone (off-label use), other benzodiazepines, quetiapine (off-label use), and doxepin.⁴¹ Overall, over-the-counter melatonin may be more widely used than any of the prescription choices.⁴²

One useful basis for selection of an agent is whether the patient complains of difficulty with sleep initiation at the beginning of the night vs sleep maintenance, or both. For sleep initiation complaints, short-acting/sleep-promoting agents are preferred. For sleep maintenance complaints, longer-acting/wake-inhibiting medications that work at the end of the sleep phase may be necessary.

The AASM has recently concluded an exhaustive review of the literature regarding hypnotic medications for chronic insomnia.⁴³ The authors acknowledge important methodologic limitations, most notably a paucity of data on effectiveness and adverse effects, along with industry sponsorship of most studies and publication bias. Nevertheless, their conclusions favor the use of FDA-approved agents to off-label use of trazodone or over-the-counter use of melatonin or diphenhydramine. To summarize the AASM guidelines:³⁸

1. Medications recommended for sleep onset insomnia include: eszopiclone, ramelteon, temazepam, triazolam, zaleplon, and zolpidem.
2. Medications recommended for treating sleep maintenance insomnia include: doxepin, eszopiclone, suvorexant, zolpidem, and temazepam.
3. Medications not recommended for treating either sleep initiation or sleep maintenance insomnia include: diphenhydramine, melatonin, tiagabine, trazodone, tryptophan, and valerian.

These recommendations are similar to a review of hypnotics published by The Medical Letter in 2015.⁴⁰
 

Trazodone, an antidepressant medication with sedating properties, is not FDA-approved for the treatment of insomnia, yet ranks second to zolpidem in the number of prescriptions written for insomnia. Its popularity may be due to a perception of safety implied by its unscheduled FDA status and the lack of restrictions on prescribing duration. However, several reviews point out that its evidence base is weak.^44,45 There is only one placebo-controlled study involving trazodone use for "primary insomnia" (other studies have been in people with comorbid depression) and it showed insignificant improvements in sleep parameters and less effectiveness compared to zolpidem.⁴⁶

Trazadone, an antidepressant with sedating properties, is not FDA-approved for the treatment of insomnia, yet ranks second to zolpidem in the number of prescriptions written for insomnia.

Trazodone’s mechanisms of action are thought to be serotonin reuptake inhibition and alpha blockade, which might explain adverse effects such as orthostatic hypotension and psychomotor impairment. The frequency of such adverse effects is difficult to estimate since most studies of trazodone have used higher doses than are commonly used for insomnia in order to address comorbid depression. However, some experts have cautioned against its use—especially in the elderly.

The AASM guidelines recommend against use of trazodone. Others assert that it is probably best reserved for people in whom the complaint of insomnia is linked to comorbid depression.^43,44 

Is long-term use ever appropriate? There are no published guidelines about dosing strategies for hypnotics and whether nightly or intermittent use is preferred. All FDA-approved hypnotic agents are for short-term use, but this designation stems from a lack of long-term studies demonstrating continuing efficacy rather than actual proof of loss of effect. Although tolerance to over-the-counter sleep aids does occur, it has not been demonstrated to occur with FDA-approved agents. Studies of eszopiclone and zolpidem indicate continuing effectiveness as hypnotics with nightly use over a time-frame of several months to one year.^47,48

Regarding the thorny question of long-term use of hypnotics for chronic insomnia, the AASM concluded that long-term use should be reserved for “individuals in whom CBT-I is inaccessible or ineffective, who have been appropriately screened for contraindications to such treatment, who maintain long-term gains with medication, and who are followed regularly.”⁴³

CORRESPONDENCE
Adam J. Sorscher, MD, Dartmouth-Hitchcock Medical Center, 18 Old Etna Road, Lebanon, NH 03766; [email protected].

Photo by Rhoda Baer

A report on cancer in the US suggests the incidence of leukemia and myeloma has been on the rise in recent years, but the incidence of non-Hodgkin lymphoma (NHL) has been on the decline.

Meanwhile, annual death rates for leukemia and NHL have decreased, and annual death rates for myeloma have decreased in men but not in women.

Furthermore, patients with leukemia, NHL, and myeloma have seen a substantial improvement in 5-year survival rates in recent years relative to patients in the late 1970s.

These findings are part of the Annual Report to the Nation on the Status of Cancer, 1975-2014, which has been published in the Journal of the National Cancer Institute.

This report is released each year, but the current edition includes a special section focused on survival.

“While trends in death rates are the most commonly used measure to assess progress against cancer, survival trends are also an important measure to evaluate progress in improvement of cancer outcomes,” said Ahmedin Jemal, DVM, PhD, of the American Cancer Society.

“We last included a special section on cancer survival in 2004, and, as we found then, survival improved over time for almost all cancers at every stage of diagnosis.”

For the current report, researchers calculated the 5-year average annual percent changes (AAPCs) for 2009 to 2013 for cancer incidence and for 2010 to 2014 for cancer mortality.

Cancer incidence (2009-2013)

In women, the AAPC increased 1.5% for leukemia (P<0.05), decreased 0.5% for NHL (P<0.05), and increased 2.2% for myeloma (P<0.05).

In men, the AAPC increased 1.7% for leukemia (P<0.05), decreased 0.2% for NHL, and increased 2.8% for myeloma (P<0.05).

Cancer mortality (2010-2014)

In women, the AAPC decreased 1.2% for leukemia (P<0.05), decreased 2.2% for NHL (P<0.05), and increased 0.5% for myeloma.

In men, the AAPC decreased 1.0% for leukemia (P<0.05), decreased 2.0% for NHL (P<0.05), and decreased 0.9% for myeloma (P<0.05).

5-year survival

The researchers compared 5-year relative survival for cancers diagnosed from 1975 to 1977 and those diagnosed from 2006 to 2012.

The absolute percentage change over time (for both sexes combined) was 26.1% for NHL, 25.7% for myeloma, and 28.5% for leukemia.

Five-year survival for patients diagnosed in 1975-1977 was 46.5% for NHL, 24.6% for myeloma, and 34.2% for leukemia.

Five-year survival for patients diagnosed in 2006-2012 was 72.6% for NHL, 50.2% for myeloma, and 62.7% for leukemia.

Photo by Rhoda Baer

A report on cancer in the US suggests the incidence of leukemia and myeloma has been on the rise in recent years, but the incidence of non-Hodgkin lymphoma (NHL) has been on the decline.

Meanwhile, annual death rates for leukemia and NHL have decreased, and annual death rates for myeloma have decreased in men but not in women.

Furthermore, patients with leukemia, NHL, and myeloma have seen a substantial improvement in 5-year survival rates in recent years relative to patients in the late 1970s.

These findings are part of the Annual Report to the Nation on the Status of Cancer, 1975-2014, which has been published in the Journal of the National Cancer Institute.

This report is released each year, but the current edition includes a special section focused on survival.

“While trends in death rates are the most commonly used measure to assess progress against cancer, survival trends are also an important measure to evaluate progress in improvement of cancer outcomes,” said Ahmedin Jemal, DVM, PhD, of the American Cancer Society.

“We last included a special section on cancer survival in 2004, and, as we found then, survival improved over time for almost all cancers at every stage of diagnosis.”

For the current report, researchers calculated the 5-year average annual percent changes (AAPCs) for 2009 to 2013 for cancer incidence and for 2010 to 2014 for cancer mortality.

Cancer incidence (2009-2013)

In women, the AAPC increased 1.5% for leukemia (P<0.05), decreased 0.5% for NHL (P<0.05), and increased 2.2% for myeloma (P<0.05).

In men, the AAPC increased 1.7% for leukemia (P<0.05), decreased 0.2% for NHL, and increased 2.8% for myeloma (P<0.05).

Cancer mortality (2010-2014)

In women, the AAPC decreased 1.2% for leukemia (P<0.05), decreased 2.2% for NHL (P<0.05), and increased 0.5% for myeloma.

In men, the AAPC decreased 1.0% for leukemia (P<0.05), decreased 2.0% for NHL (P<0.05), and decreased 0.9% for myeloma (P<0.05).

5-year survival

The researchers compared 5-year relative survival for cancers diagnosed from 1975 to 1977 and those diagnosed from 2006 to 2012.

The absolute percentage change over time (for both sexes combined) was 26.1% for NHL, 25.7% for myeloma, and 28.5% for leukemia.

Five-year survival for patients diagnosed in 1975-1977 was 46.5% for NHL, 24.6% for myeloma, and 34.2% for leukemia.

Five-year survival for patients diagnosed in 2006-2012 was 72.6% for NHL, 50.2% for myeloma, and 62.7% for leukemia.

Photo by Rhoda Baer

A report on cancer in the US suggests the incidence of leukemia and myeloma has been on the rise in recent years, but the incidence of non-Hodgkin lymphoma (NHL) has been on the decline.

Meanwhile, annual death rates for leukemia and NHL have decreased, and annual death rates for myeloma have decreased in men but not in women.

Furthermore, patients with leukemia, NHL, and myeloma have seen a substantial improvement in 5-year survival rates in recent years relative to patients in the late 1970s.

These findings are part of the Annual Report to the Nation on the Status of Cancer, 1975-2014, which has been published in the Journal of the National Cancer Institute.

This report is released each year, but the current edition includes a special section focused on survival.

“While trends in death rates are the most commonly used measure to assess progress against cancer, survival trends are also an important measure to evaluate progress in improvement of cancer outcomes,” said Ahmedin Jemal, DVM, PhD, of the American Cancer Society.

“We last included a special section on cancer survival in 2004, and, as we found then, survival improved over time for almost all cancers at every stage of diagnosis.”

For the current report, researchers calculated the 5-year average annual percent changes (AAPCs) for 2009 to 2013 for cancer incidence and for 2010 to 2014 for cancer mortality.

Cancer incidence (2009-2013)

In women, the AAPC increased 1.5% for leukemia (P<0.05), decreased 0.5% for NHL (P<0.05), and increased 2.2% for myeloma (P<0.05).

In men, the AAPC increased 1.7% for leukemia (P<0.05), decreased 0.2% for NHL, and increased 2.8% for myeloma (P<0.05).

Cancer mortality (2010-2014)

In women, the AAPC decreased 1.2% for leukemia (P<0.05), decreased 2.2% for NHL (P<0.05), and increased 0.5% for myeloma.

In men, the AAPC decreased 1.0% for leukemia (P<0.05), decreased 2.0% for NHL (P<0.05), and decreased 0.9% for myeloma (P<0.05).

5-year survival

The researchers compared 5-year relative survival for cancers diagnosed from 1975 to 1977 and those diagnosed from 2006 to 2012.

The absolute percentage change over time (for both sexes combined) was 26.1% for NHL, 25.7% for myeloma, and 28.5% for leukemia.

Five-year survival for patients diagnosed in 1975-1977 was 46.5% for NHL, 24.6% for myeloma, and 34.2% for leukemia.

Five-year survival for patients diagnosed in 2006-2012 was 72.6% for NHL, 50.2% for myeloma, and 62.7% for leukemia.

Influenza vaccination was associated with reduced risk of laboratory-confirmed influenza-associated death in children, a case-cohort analysis found.

“These results support current recommendations for annual influenza vaccination for all children 6 months of age” and older, wrote Brendan Flannery, PhD, and his coauthors at the Centers for Disease Control and Prevention, Atlanta. “To our knowledge, this is the first study to use laboratory-confirmed outcomes to investigate influenza vaccine effectiveness against influenza-associated deaths.”

KatarzynaBialasiewicz/Thinkstock

[email protected]

Influenza vaccination was associated with reduced risk of laboratory-confirmed influenza-associated death in children, a case-cohort analysis found.

“These results support current recommendations for annual influenza vaccination for all children 6 months of age” and older, wrote Brendan Flannery, PhD, and his coauthors at the Centers for Disease Control and Prevention, Atlanta. “To our knowledge, this is the first study to use laboratory-confirmed outcomes to investigate influenza vaccine effectiveness against influenza-associated deaths.”

KatarzynaBialasiewicz/Thinkstock

[email protected]

Influenza vaccination was associated with reduced risk of laboratory-confirmed influenza-associated death in children, a case-cohort analysis found.

“These results support current recommendations for annual influenza vaccination for all children 6 months of age” and older, wrote Brendan Flannery, PhD, and his coauthors at the Centers for Disease Control and Prevention, Atlanta. “To our knowledge, this is the first study to use laboratory-confirmed outcomes to investigate influenza vaccine effectiveness against influenza-associated deaths.”

KatarzynaBialasiewicz/Thinkstock

[email protected]

Mentorship, whether through a formal or informal system, plays a significant role in a professional’s life; it fosters the development of professional expertise and is associated with increased job satisfaction. An effective mentor guides a less-experienced colleague by modeling positive behaviors and building trust, while being cognizant that his or her role is to be dependable, engaged, authentic, and attuned to the needs of the mentee. You can probably name one of your mentors off the top of your head right now!

The original “mentor” was a character of that name in Homer’s epic poem The Odyssey, but the word is now used to refer to a trusted advisor, friend, teacher, or wise person. In the story, Mentor served as a friend and advocate to Telemachus, the son of the king of Ithaca, while his father, Odysseus, was away fighting in the Trojan War. In 1699, the novel The Adventures of Telemachus portrayed Mentor as Telemachus’ tutor, and he became the hero of the story.^1,2

History holds many examples of mentoring relationships: Socrates and Plato, Haydn and Beethoven, and Freud and Jung. Modern-day duos include Kobe Bryant and Shaquille O’Neal, Kirk and Spock, and—dare I say it?—Brady and Belichick. During the Middle Ages, mentorship—particularly in medicine and nursing—was practiced via apprenticeship, which incorporated support, guidance, socialization, well-being, empowerment, education, and career progression.³

Throughout my career as a PA, I have been fortunate to be guided by competent and willing mentors. What have they had in common? For starters, an internal desire (sometimes called generosity of spirit) to mentor and a commitment to my growth and development as their mentee. Successful professional mentors must also possess the necessary knowledge to help effectively develop their mentee’s skills. Discussions with my colleagues and previous mentors inspired the following compilation of the essential responsibilities and traits of a mentor.

Initiating new ideas. A main aspect of a mentor’s role involves assisting in acquiring the confidence and tools to function and excel in our competitive professional world.^4-6 In the early 1970s, when I was a young PA, a wonderful physician and friend, Dr. Burton Brasher, took me under his wing and exemplified what it means to be a clinician. I learned from him that it was also my obligation to mentor others, and I have tried to do this frequently in my four decades as a PA. Through his example, I was shown the importance of cultivating emotional intelligence and sensitivity while still providing an honest assessment of strengths and weaknesses. Here was a physician who was unencumbered by ego. We met often to discuss the care of both of our patients.

Staying the course. In 1995, I mentored James Cannon—a young financial comptroller who desperately wanted to be a PA. I’ve (hopefully) helped him navigate PA school, our mutual time in the military, his time in academia, and his introduction to professional volunteer work. In each stage of his career, we had lengthy conversations about the pros and cons of his decisions. Now, 22 years later, he has become my mentor; he has matured in the profession and is at the forefront of taking it to the next level. It is now very common for me to call on him for his advice as I move into the home stretch of my career. A few years ago, he became a trustee of our university and his skills have advanced the success of our programs. Indeed, the student becomes the teacher.

Networking and articulating cultural norms. Dave Mittman, the co-founder and original publisher of Clinician Reviews, had the experience of hiring his very close friend and PA school classmate, Tom Yackeren. In 1985, Dave was publisher of Physician Assistant Journal (at that time, the official journal of the AAPA). Dave and Tom were business partners and relied on each other’s skills to grow their business. They shared trust, friendship, and a mutual knowledge of professional “culture.” They understood each other and how they could each contribute to their success. Their partnership maintained a complementary balance, each of them able to play to his strengths with the support and encouragement of the other. Tom has since used his knowledge and experience to mentor others.

Demonstrating honesty, integrity, and enthusiasm. Marie-Eileen Onieal, our NP editor-in-chief, grew up in a household where her father was a firefighter and union organizer. He taught her the value of always paying it forward. While she has mentored many people in her career, she fondly remembers mentoring Lori Fritz through her transition into academia—what Marie-Eileen calls “the precarious journey of an educator.” When she met Lori, she says, they just “clicked,” and that bond has survived to this day. Lori is now an established academician, mentoring new students and professionals, and modeling her experience with Marie-Eileen’s involvement in the profession.

These are examples of when it works. But what happens when the relationship doesn’t “click”? Unfortunately, not all mentorships are fruitful. When mentor and mentee clash, it is paramount to acknowledge that the relationship is not working and to back away appropriately, without regard to ego. No one benefits when the parties are at odds—and this may explain why some of the greatest partnerships form organically.

Above all, in order for a mentorship to be prosperous, mentors must express compassion and remain genuine throughout all interactions with their mentee. It is a long-term commitment. Without this generosity of spirit, the influence and benefit of a professional mentor would be lost. If you have other ideas about what makes a great mentor, or how to foster a more satisfying mentor/mentee relationship, please share them with me at [email protected].

Mentorship, whether through a formal or informal system, plays a significant role in a professional’s life; it fosters the development of professional expertise and is associated with increased job satisfaction. An effective mentor guides a less-experienced colleague by modeling positive behaviors and building trust, while being cognizant that his or her role is to be dependable, engaged, authentic, and attuned to the needs of the mentee. You can probably name one of your mentors off the top of your head right now!

The original “mentor” was a character of that name in Homer’s epic poem The Odyssey, but the word is now used to refer to a trusted advisor, friend, teacher, or wise person. In the story, Mentor served as a friend and advocate to Telemachus, the son of the king of Ithaca, while his father, Odysseus, was away fighting in the Trojan War. In 1699, the novel The Adventures of Telemachus portrayed Mentor as Telemachus’ tutor, and he became the hero of the story.^1,2

History holds many examples of mentoring relationships: Socrates and Plato, Haydn and Beethoven, and Freud and Jung. Modern-day duos include Kobe Bryant and Shaquille O’Neal, Kirk and Spock, and—dare I say it?—Brady and Belichick. During the Middle Ages, mentorship—particularly in medicine and nursing—was practiced via apprenticeship, which incorporated support, guidance, socialization, well-being, empowerment, education, and career progression.³

Throughout my career as a PA, I have been fortunate to be guided by competent and willing mentors. What have they had in common? For starters, an internal desire (sometimes called generosity of spirit) to mentor and a commitment to my growth and development as their mentee. Successful professional mentors must also possess the necessary knowledge to help effectively develop their mentee’s skills. Discussions with my colleagues and previous mentors inspired the following compilation of the essential responsibilities and traits of a mentor.

Initiating new ideas. A main aspect of a mentor’s role involves assisting in acquiring the confidence and tools to function and excel in our competitive professional world.^4-6 In the early 1970s, when I was a young PA, a wonderful physician and friend, Dr. Burton Brasher, took me under his wing and exemplified what it means to be a clinician. I learned from him that it was also my obligation to mentor others, and I have tried to do this frequently in my four decades as a PA. Through his example, I was shown the importance of cultivating emotional intelligence and sensitivity while still providing an honest assessment of strengths and weaknesses. Here was a physician who was unencumbered by ego. We met often to discuss the care of both of our patients.

Staying the course. In 1995, I mentored James Cannon—a young financial comptroller who desperately wanted to be a PA. I’ve (hopefully) helped him navigate PA school, our mutual time in the military, his time in academia, and his introduction to professional volunteer work. In each stage of his career, we had lengthy conversations about the pros and cons of his decisions. Now, 22 years later, he has become my mentor; he has matured in the profession and is at the forefront of taking it to the next level. It is now very common for me to call on him for his advice as I move into the home stretch of my career. A few years ago, he became a trustee of our university and his skills have advanced the success of our programs. Indeed, the student becomes the teacher.

Networking and articulating cultural norms. Dave Mittman, the co-founder and original publisher of Clinician Reviews, had the experience of hiring his very close friend and PA school classmate, Tom Yackeren. In 1985, Dave was publisher of Physician Assistant Journal (at that time, the official journal of the AAPA). Dave and Tom were business partners and relied on each other’s skills to grow their business. They shared trust, friendship, and a mutual knowledge of professional “culture.” They understood each other and how they could each contribute to their success. Their partnership maintained a complementary balance, each of them able to play to his strengths with the support and encouragement of the other. Tom has since used his knowledge and experience to mentor others.

Demonstrating honesty, integrity, and enthusiasm. Marie-Eileen Onieal, our NP editor-in-chief, grew up in a household where her father was a firefighter and union organizer. He taught her the value of always paying it forward. While she has mentored many people in her career, she fondly remembers mentoring Lori Fritz through her transition into academia—what Marie-Eileen calls “the precarious journey of an educator.” When she met Lori, she says, they just “clicked,” and that bond has survived to this day. Lori is now an established academician, mentoring new students and professionals, and modeling her experience with Marie-Eileen’s involvement in the profession.

These are examples of when it works. But what happens when the relationship doesn’t “click”? Unfortunately, not all mentorships are fruitful. When mentor and mentee clash, it is paramount to acknowledge that the relationship is not working and to back away appropriately, without regard to ego. No one benefits when the parties are at odds—and this may explain why some of the greatest partnerships form organically.

Above all, in order for a mentorship to be prosperous, mentors must express compassion and remain genuine throughout all interactions with their mentee. It is a long-term commitment. Without this generosity of spirit, the influence and benefit of a professional mentor would be lost. If you have other ideas about what makes a great mentor, or how to foster a more satisfying mentor/mentee relationship, please share them with me at [email protected].

Mentorship, whether through a formal or informal system, plays a significant role in a professional’s life; it fosters the development of professional expertise and is associated with increased job satisfaction. An effective mentor guides a less-experienced colleague by modeling positive behaviors and building trust, while being cognizant that his or her role is to be dependable, engaged, authentic, and attuned to the needs of the mentee. You can probably name one of your mentors off the top of your head right now!

The original “mentor” was a character of that name in Homer’s epic poem The Odyssey, but the word is now used to refer to a trusted advisor, friend, teacher, or wise person. In the story, Mentor served as a friend and advocate to Telemachus, the son of the king of Ithaca, while his father, Odysseus, was away fighting in the Trojan War. In 1699, the novel The Adventures of Telemachus portrayed Mentor as Telemachus’ tutor, and he became the hero of the story.^1,2

History holds many examples of mentoring relationships: Socrates and Plato, Haydn and Beethoven, and Freud and Jung. Modern-day duos include Kobe Bryant and Shaquille O’Neal, Kirk and Spock, and—dare I say it?—Brady and Belichick. During the Middle Ages, mentorship—particularly in medicine and nursing—was practiced via apprenticeship, which incorporated support, guidance, socialization, well-being, empowerment, education, and career progression.³

Throughout my career as a PA, I have been fortunate to be guided by competent and willing mentors. What have they had in common? For starters, an internal desire (sometimes called generosity of spirit) to mentor and a commitment to my growth and development as their mentee. Successful professional mentors must also possess the necessary knowledge to help effectively develop their mentee’s skills. Discussions with my colleagues and previous mentors inspired the following compilation of the essential responsibilities and traits of a mentor.

Initiating new ideas. A main aspect of a mentor’s role involves assisting in acquiring the confidence and tools to function and excel in our competitive professional world.^4-6 In the early 1970s, when I was a young PA, a wonderful physician and friend, Dr. Burton Brasher, took me under his wing and exemplified what it means to be a clinician. I learned from him that it was also my obligation to mentor others, and I have tried to do this frequently in my four decades as a PA. Through his example, I was shown the importance of cultivating emotional intelligence and sensitivity while still providing an honest assessment of strengths and weaknesses. Here was a physician who was unencumbered by ego. We met often to discuss the care of both of our patients.

Staying the course. In 1995, I mentored James Cannon—a young financial comptroller who desperately wanted to be a PA. I’ve (hopefully) helped him navigate PA school, our mutual time in the military, his time in academia, and his introduction to professional volunteer work. In each stage of his career, we had lengthy conversations about the pros and cons of his decisions. Now, 22 years later, he has become my mentor; he has matured in the profession and is at the forefront of taking it to the next level. It is now very common for me to call on him for his advice as I move into the home stretch of my career. A few years ago, he became a trustee of our university and his skills have advanced the success of our programs. Indeed, the student becomes the teacher.

Networking and articulating cultural norms. Dave Mittman, the co-founder and original publisher of Clinician Reviews, had the experience of hiring his very close friend and PA school classmate, Tom Yackeren. In 1985, Dave was publisher of Physician Assistant Journal (at that time, the official journal of the AAPA). Dave and Tom were business partners and relied on each other’s skills to grow their business. They shared trust, friendship, and a mutual knowledge of professional “culture.” They understood each other and how they could each contribute to their success. Their partnership maintained a complementary balance, each of them able to play to his strengths with the support and encouragement of the other. Tom has since used his knowledge and experience to mentor others.

Demonstrating honesty, integrity, and enthusiasm. Marie-Eileen Onieal, our NP editor-in-chief, grew up in a household where her father was a firefighter and union organizer. He taught her the value of always paying it forward. While she has mentored many people in her career, she fondly remembers mentoring Lori Fritz through her transition into academia—what Marie-Eileen calls “the precarious journey of an educator.” When she met Lori, she says, they just “clicked,” and that bond has survived to this day. Lori is now an established academician, mentoring new students and professionals, and modeling her experience with Marie-Eileen’s involvement in the profession.

These are examples of when it works. But what happens when the relationship doesn’t “click”? Unfortunately, not all mentorships are fruitful. When mentor and mentee clash, it is paramount to acknowledge that the relationship is not working and to back away appropriately, without regard to ego. No one benefits when the parties are at odds—and this may explain why some of the greatest partnerships form organically.

Above all, in order for a mentorship to be prosperous, mentors must express compassion and remain genuine throughout all interactions with their mentee. It is a long-term commitment. Without this generosity of spirit, the influence and benefit of a professional mentor would be lost. If you have other ideas about what makes a great mentor, or how to foster a more satisfying mentor/mentee relationship, please share them with me at [email protected].