A recombinant factor VIII Fc fusion protein (rFVIIIFc/efmoroctocog alfa, Eloctate/Elocta) can prevent and control bleeding in previously treated children with severe hemophilia A, results of the phase 3 KIDS A-LONG study suggest.

Children who were previously receiving factor VIII prophylaxis saw their median annualized bleeding rate (ABR) decrease with rFVIIIFc, and close to half of the children on this study did not have any bleeding episodes while they were receiving rFVIIIFc.

None of the patients developed inhibitors to rFVIIIFc. And researchers said adverse events on this trial were typical of a pediatric hemophilia population.

The team reported these results in the Journal of Thrombosis and Haemostasis. The trial was sponsored by Biogen Idec and Sobi, the companies developing rFVIIIFc.

The study included 71 boys younger than 12 years of age who had severe hemophilia A. The patients had at least 50 prior exposure days to factor VIII and no history of factor VIII inhibitors.

The children were set to receive twice-weekly prophylactic infusions of rFVIIIFc, 25 IU/kg on day 1 and 50 IU/kg on day 4, but the researchers made adjustments to dosing as needed.

The median average weekly rFVIIIFc prophylactic dose was 88.11 IU kg. About 90% of the patients were on twice-weekly dosing at the end of the study. Seventy-four percent of patients were able to reduce their dosing frequency with rFVIIIFc compared to factor VIII prophylaxis.

About 46% of patients did not have any bleeding events on study. The median ABR was 1.96 overall and 0 for spontaneous and traumatic bleeding episodes, as well as for spontaneous joint bleeding episodes.

Among patients who were previously receiving factor VIII prophylaxis, their median ABR decreased with rFVIIIFc. For children younger than 6 years of age, the median ABR fell from 1.50 to 0. For children ages 6 through 11, the median ABR fell from 2.50 to 2.01.

About 86% of patients had at least one adverse event while on rFVIIIFc, but none of them discontinued treatment as a result.

Two non-serious events (myalgia and erythematous rash) were considered related to rFVIIIFc. And 5 patients experienced 7 serious adverse events that were not related to treatment.

A recombinant factor VIII Fc fusion protein (rFVIIIFc/efmoroctocog alfa, Eloctate/Elocta) can prevent and control bleeding in previously treated children with severe hemophilia A, results of the phase 3 KIDS A-LONG study suggest.

Children who were previously receiving factor VIII prophylaxis saw their median annualized bleeding rate (ABR) decrease with rFVIIIFc, and close to half of the children on this study did not have any bleeding episodes while they were receiving rFVIIIFc.

None of the patients developed inhibitors to rFVIIIFc. And researchers said adverse events on this trial were typical of a pediatric hemophilia population.

The team reported these results in the Journal of Thrombosis and Haemostasis. The trial was sponsored by Biogen Idec and Sobi, the companies developing rFVIIIFc.

The study included 71 boys younger than 12 years of age who had severe hemophilia A. The patients had at least 50 prior exposure days to factor VIII and no history of factor VIII inhibitors.

The children were set to receive twice-weekly prophylactic infusions of rFVIIIFc, 25 IU/kg on day 1 and 50 IU/kg on day 4, but the researchers made adjustments to dosing as needed.

The median average weekly rFVIIIFc prophylactic dose was 88.11 IU kg. About 90% of the patients were on twice-weekly dosing at the end of the study. Seventy-four percent of patients were able to reduce their dosing frequency with rFVIIIFc compared to factor VIII prophylaxis.

About 46% of patients did not have any bleeding events on study. The median ABR was 1.96 overall and 0 for spontaneous and traumatic bleeding episodes, as well as for spontaneous joint bleeding episodes.

Among patients who were previously receiving factor VIII prophylaxis, their median ABR decreased with rFVIIIFc. For children younger than 6 years of age, the median ABR fell from 1.50 to 0. For children ages 6 through 11, the median ABR fell from 2.50 to 2.01.

About 86% of patients had at least one adverse event while on rFVIIIFc, but none of them discontinued treatment as a result.

Two non-serious events (myalgia and erythematous rash) were considered related to rFVIIIFc. And 5 patients experienced 7 serious adverse events that were not related to treatment.

A recombinant factor VIII Fc fusion protein (rFVIIIFc/efmoroctocog alfa, Eloctate/Elocta) can prevent and control bleeding in previously treated children with severe hemophilia A, results of the phase 3 KIDS A-LONG study suggest.

Children who were previously receiving factor VIII prophylaxis saw their median annualized bleeding rate (ABR) decrease with rFVIIIFc, and close to half of the children on this study did not have any bleeding episodes while they were receiving rFVIIIFc.

None of the patients developed inhibitors to rFVIIIFc. And researchers said adverse events on this trial were typical of a pediatric hemophilia population.

The team reported these results in the Journal of Thrombosis and Haemostasis. The trial was sponsored by Biogen Idec and Sobi, the companies developing rFVIIIFc.

The study included 71 boys younger than 12 years of age who had severe hemophilia A. The patients had at least 50 prior exposure days to factor VIII and no history of factor VIII inhibitors.

The children were set to receive twice-weekly prophylactic infusions of rFVIIIFc, 25 IU/kg on day 1 and 50 IU/kg on day 4, but the researchers made adjustments to dosing as needed.

The median average weekly rFVIIIFc prophylactic dose was 88.11 IU kg. About 90% of the patients were on twice-weekly dosing at the end of the study. Seventy-four percent of patients were able to reduce their dosing frequency with rFVIIIFc compared to factor VIII prophylaxis.

About 46% of patients did not have any bleeding events on study. The median ABR was 1.96 overall and 0 for spontaneous and traumatic bleeding episodes, as well as for spontaneous joint bleeding episodes.

Among patients who were previously receiving factor VIII prophylaxis, their median ABR decreased with rFVIIIFc. For children younger than 6 years of age, the median ABR fell from 1.50 to 0. For children ages 6 through 11, the median ABR fell from 2.50 to 2.01.

About 86% of patients had at least one adverse event while on rFVIIIFc, but none of them discontinued treatment as a result.

Two non-serious events (myalgia and erythematous rash) were considered related to rFVIIIFc. And 5 patients experienced 7 serious adverse events that were not related to treatment.

The pharmaceutical company Mylan is conducting a US-wide recall of several injectable chemotherapy drugs.

Testing of retention samples revealed foreign particulate matter in lots of gemcitabine, carboplatin, methotrexate, and cytarabine. So Mylan issued a

recall of these lots to the hospital/user level.

To date, Mylan has not received any reports of adverse events related to this recall. However, administering injectables that contain foreign particulates can have severe consequences.

Intrathecal administration could result in a life-threatening adverse event or permanent impairment of a body function. Intravenous administration has the potential to damage and/or obstruct blood vessels, which could induce emboli, particularly in the lungs. Intravenous injection can also result in local inflammation, phlebitis, allergic response, and/or embolization in the body and infection.

Intra-arterial administration could result in damage to blood vessels in the distal extremities or organs. And intramuscular administration could result in foreign-body inflammatory response, with local pain, swelling, and possible long-term granuloma formation.

Recall details

The following drugs are included in this recall:

• Gemcitabine for Injection, USP 200 mg; 10 mL; NDC number: 67457-464-20; Lot number: 7801396; Expiration date: 08/2016
• Gemcitabine for Injection, USP 200 mg; 10 mL; NDC number: 67457-464-20; Lot number: 7801401; Expiration date: 08/2016
• Gemcitabine for Injection, USP 200 mg; 10 mL; NDC number: 0069-3857-10; Lot number: 7801089; Expiration date: 07/2015
• Gemcitabine for Injection, USP 2 g; 100 mL; NDC number: 67457-463-02; Lot number: 7801222; Expiration date: 03/2016
• Gemcitabine for Injection, USP 1 g; 50 mL; NDC number: 67457-462-01; Lot number: 7801273;        Expiration date: 05/2016
• Carboplatin Injection 10 mg/mL; 100 mL; NDC number: 67457-493-46; Lot number: 7801312; Expiration date: 06/2015
• Methotrexate Injection, USP 25 mg/mL; 2 mL (5 x 2 mL); NDC number: 0069-0146-02; Lot number: 7801082; Expiration date: 07/2015
• Cytarabine Injection 20 mg/mL; 5 mL (10 x 5mL); NDC number: 0069-0152-02; Lot number: 7801050; Expiration date: 05/2015.

Gemcitabine for Injection, USP 200 mg is an intravenously administered product indicated for the treatment of ovarian cancer, breast cancer, non-small cell lung cancer, and pancreatic cancer. These lots were distributed in the US between February 18, 2014, and December 19, 2014, and were manufactured and packaged by Agila Onco Therapies Limited, a Mylan company. Lot 7801089 is packaged with a Pfizer Injectable label.

Carboplatin Injection 10 mg/mL is an intravenously administered product indicated for the treatment of advanced ovarian carcinoma. The lot was distributed in the US between August 11, 2014, and October 7, 2014, and was packaged by Agila Onco Therapies Limited, a Mylan company, with a Mylan Institutional label.

Methotrexate Injection, USP 25 mg/mL can be administered intramuscularly, intravenously, intra-arterially, or intrathecally and is indicated for certain neoplastic diseases, severe psoriasis, and adult rheumatoid arthritis. The lot was distributed in the US between January 16, 2014, and March 25, 2014, and was packaged by Agila Onco Therapies Limited, a Mylan company, with a Pfizer Injectables label.

Cytarabine Injection can be administered intravenously or intrathecally and in combination with other approved anticancer drugs. Cytarabine is indicated for remission induction in acute non-lymphocytic leukemia in adults and pediatric patients. The lot was distributed in the US between May 02, 2014, and July 24, 2014, and was manufactured and packaged by Agila Onco Therapies Limited, a Mylan company located in Bangalore, India, and is packaged with a Pfizer Injectables label.

Mylan is notifying its distributors and customers by letter and is arranging for the return of all recalled products. Distributors, retailers, hospitals, clinics, and physicians with the recalled products should stop using them and return them to the place of purchase.

 

Consumers with questions regarding this recall can contact Mylan Customer Relations at 1-800-796-9526 or [email protected], Monday through Friday from 8 am to 5 pm EST.

Consumers should contact their physicians or healthcare providers if they have experienced any problems that may be related to using these drugs.

Adverse reactions or quality problems related to the use of these product may be reported to the US Food and Drug Administration’s MedWatch Adverse Event Reporting Program.

The pharmaceutical company Mylan is conducting a US-wide recall of several injectable chemotherapy drugs.

Testing of retention samples revealed foreign particulate matter in lots of gemcitabine, carboplatin, methotrexate, and cytarabine. So Mylan issued a

recall of these lots to the hospital/user level.

To date, Mylan has not received any reports of adverse events related to this recall. However, administering injectables that contain foreign particulates can have severe consequences.

Intrathecal administration could result in a life-threatening adverse event or permanent impairment of a body function. Intravenous administration has the potential to damage and/or obstruct blood vessels, which could induce emboli, particularly in the lungs. Intravenous injection can also result in local inflammation, phlebitis, allergic response, and/or embolization in the body and infection.

Intra-arterial administration could result in damage to blood vessels in the distal extremities or organs. And intramuscular administration could result in foreign-body inflammatory response, with local pain, swelling, and possible long-term granuloma formation.

Recall details

The following drugs are included in this recall:

• Gemcitabine for Injection, USP 200 mg; 10 mL; NDC number: 67457-464-20; Lot number: 7801396; Expiration date: 08/2016
• Gemcitabine for Injection, USP 200 mg; 10 mL; NDC number: 67457-464-20; Lot number: 7801401; Expiration date: 08/2016
• Gemcitabine for Injection, USP 200 mg; 10 mL; NDC number: 0069-3857-10; Lot number: 7801089; Expiration date: 07/2015
• Gemcitabine for Injection, USP 2 g; 100 mL; NDC number: 67457-463-02; Lot number: 7801222; Expiration date: 03/2016
• Gemcitabine for Injection, USP 1 g; 50 mL; NDC number: 67457-462-01; Lot number: 7801273;        Expiration date: 05/2016
• Carboplatin Injection 10 mg/mL; 100 mL; NDC number: 67457-493-46; Lot number: 7801312; Expiration date: 06/2015
• Methotrexate Injection, USP 25 mg/mL; 2 mL (5 x 2 mL); NDC number: 0069-0146-02; Lot number: 7801082; Expiration date: 07/2015
• Cytarabine Injection 20 mg/mL; 5 mL (10 x 5mL); NDC number: 0069-0152-02; Lot number: 7801050; Expiration date: 05/2015.

Gemcitabine for Injection, USP 200 mg is an intravenously administered product indicated for the treatment of ovarian cancer, breast cancer, non-small cell lung cancer, and pancreatic cancer. These lots were distributed in the US between February 18, 2014, and December 19, 2014, and were manufactured and packaged by Agila Onco Therapies Limited, a Mylan company. Lot 7801089 is packaged with a Pfizer Injectable label.

Carboplatin Injection 10 mg/mL is an intravenously administered product indicated for the treatment of advanced ovarian carcinoma. The lot was distributed in the US between August 11, 2014, and October 7, 2014, and was packaged by Agila Onco Therapies Limited, a Mylan company, with a Mylan Institutional label.

Methotrexate Injection, USP 25 mg/mL can be administered intramuscularly, intravenously, intra-arterially, or intrathecally and is indicated for certain neoplastic diseases, severe psoriasis, and adult rheumatoid arthritis. The lot was distributed in the US between January 16, 2014, and March 25, 2014, and was packaged by Agila Onco Therapies Limited, a Mylan company, with a Pfizer Injectables label.

Cytarabine Injection can be administered intravenously or intrathecally and in combination with other approved anticancer drugs. Cytarabine is indicated for remission induction in acute non-lymphocytic leukemia in adults and pediatric patients. The lot was distributed in the US between May 02, 2014, and July 24, 2014, and was manufactured and packaged by Agila Onco Therapies Limited, a Mylan company located in Bangalore, India, and is packaged with a Pfizer Injectables label.

Mylan is notifying its distributors and customers by letter and is arranging for the return of all recalled products. Distributors, retailers, hospitals, clinics, and physicians with the recalled products should stop using them and return them to the place of purchase.

 

Consumers with questions regarding this recall can contact Mylan Customer Relations at 1-800-796-9526 or [email protected], Monday through Friday from 8 am to 5 pm EST.

Consumers should contact their physicians or healthcare providers if they have experienced any problems that may be related to using these drugs.

Adverse reactions or quality problems related to the use of these product may be reported to the US Food and Drug Administration’s MedWatch Adverse Event Reporting Program.

The pharmaceutical company Mylan is conducting a US-wide recall of several injectable chemotherapy drugs.

Testing of retention samples revealed foreign particulate matter in lots of gemcitabine, carboplatin, methotrexate, and cytarabine. So Mylan issued a

recall of these lots to the hospital/user level.

To date, Mylan has not received any reports of adverse events related to this recall. However, administering injectables that contain foreign particulates can have severe consequences.

Intrathecal administration could result in a life-threatening adverse event or permanent impairment of a body function. Intravenous administration has the potential to damage and/or obstruct blood vessels, which could induce emboli, particularly in the lungs. Intravenous injection can also result in local inflammation, phlebitis, allergic response, and/or embolization in the body and infection.

Intra-arterial administration could result in damage to blood vessels in the distal extremities or organs. And intramuscular administration could result in foreign-body inflammatory response, with local pain, swelling, and possible long-term granuloma formation.

Recall details

The following drugs are included in this recall:

• Gemcitabine for Injection, USP 200 mg; 10 mL; NDC number: 67457-464-20; Lot number: 7801396; Expiration date: 08/2016
• Gemcitabine for Injection, USP 200 mg; 10 mL; NDC number: 67457-464-20; Lot number: 7801401; Expiration date: 08/2016
• Gemcitabine for Injection, USP 200 mg; 10 mL; NDC number: 0069-3857-10; Lot number: 7801089; Expiration date: 07/2015
• Gemcitabine for Injection, USP 2 g; 100 mL; NDC number: 67457-463-02; Lot number: 7801222; Expiration date: 03/2016
• Gemcitabine for Injection, USP 1 g; 50 mL; NDC number: 67457-462-01; Lot number: 7801273;        Expiration date: 05/2016
• Carboplatin Injection 10 mg/mL; 100 mL; NDC number: 67457-493-46; Lot number: 7801312; Expiration date: 06/2015
• Methotrexate Injection, USP 25 mg/mL; 2 mL (5 x 2 mL); NDC number: 0069-0146-02; Lot number: 7801082; Expiration date: 07/2015
• Cytarabine Injection 20 mg/mL; 5 mL (10 x 5mL); NDC number: 0069-0152-02; Lot number: 7801050; Expiration date: 05/2015.

Gemcitabine for Injection, USP 200 mg is an intravenously administered product indicated for the treatment of ovarian cancer, breast cancer, non-small cell lung cancer, and pancreatic cancer. These lots were distributed in the US between February 18, 2014, and December 19, 2014, and were manufactured and packaged by Agila Onco Therapies Limited, a Mylan company. Lot 7801089 is packaged with a Pfizer Injectable label.

Carboplatin Injection 10 mg/mL is an intravenously administered product indicated for the treatment of advanced ovarian carcinoma. The lot was distributed in the US between August 11, 2014, and October 7, 2014, and was packaged by Agila Onco Therapies Limited, a Mylan company, with a Mylan Institutional label.

Methotrexate Injection, USP 25 mg/mL can be administered intramuscularly, intravenously, intra-arterially, or intrathecally and is indicated for certain neoplastic diseases, severe psoriasis, and adult rheumatoid arthritis. The lot was distributed in the US between January 16, 2014, and March 25, 2014, and was packaged by Agila Onco Therapies Limited, a Mylan company, with a Pfizer Injectables label.

Cytarabine Injection can be administered intravenously or intrathecally and in combination with other approved anticancer drugs. Cytarabine is indicated for remission induction in acute non-lymphocytic leukemia in adults and pediatric patients. The lot was distributed in the US between May 02, 2014, and July 24, 2014, and was manufactured and packaged by Agila Onco Therapies Limited, a Mylan company located in Bangalore, India, and is packaged with a Pfizer Injectables label.

Mylan is notifying its distributors and customers by letter and is arranging for the return of all recalled products. Distributors, retailers, hospitals, clinics, and physicians with the recalled products should stop using them and return them to the place of purchase.

 

Consumers with questions regarding this recall can contact Mylan Customer Relations at 1-800-796-9526 or [email protected], Monday through Friday from 8 am to 5 pm EST.

Consumers should contact their physicians or healthcare providers if they have experienced any problems that may be related to using these drugs.

Adverse reactions or quality problems related to the use of these product may be reported to the US Food and Drug Administration’s MedWatch Adverse Event Reporting Program.

KISSIMMEE, FLA. – Fractional carbon dioxide laser resurfacing followed by 30 minutes of aminolevulinic acid plus blue light photodynamic therapy cleared 94% of actinic keratoses, significantly more than ALA-PDT alone, according to the findings of a randomized, single-blinded, split-face study of 20 patients.

Laser resurfacing was associated with worse short-term erythema, but erythema resolved in about 7 days and was not associated with other adverse events, Dr. Macrene Alexiades-Armenakas said at the annual meeting of the American Society for Laser Medicine and Surgery.

Historically, two sessions of 20% topical ALA and blue light PDT have yielded actinic keratosis cure rates of 78% to 89%, but only with ALA incubation times of 14-18 hours, said Dr. Alexiades-Armenakas, associate clinical professor at Yale University, New Haven, Conn.

©Dr-Strangelove/ThinkStockPhotos.com

“Increasing drug penetration may serve to enhance PDT efficacy and shorten incubation time,” she said.

To test that hypothesis, she compared the safety and efficacy of 15- and 30-minute incubations of ALA and blue light PDT, with or without CO₂ laser resurfacing. After cleaning patients’ faces with acetone wipes and applying a topical anesthetic for 1 hour, she randomly selected one half of each patient’s face for pretreatment with fractional CO₂ laser, using settings of 15-28 W, 500 mcm dot spacing, and 600-800 microsecond dwell time.

Next, she applied 5-ALA to the entire face, then performed blue light illumination for 1,000 seconds. Half of the 20 patients were randomly assigned ALA incubation times of 15 minutes, while the other half underwent 30-minute incubations. She rechecked patients at 1 week, 4 weeks, and 8 weeks, and took digital photographs at baseline and at each recheck using identical lighting conditions. A blinded evaluator scored each side of each face, defining clearance as complete regression of actinic keratosis.

At 8 weeks, the rate of complete clearance for the 10 patients who underwent 15-minute ALA incubations was 88% for laser resurfacing followed by ALA-PDT, compared with 74% for ALA-PDT alone (P < .05), Dr. Alexiades-Armenakas reported. Clearance rates for the 30-minute incubation group were 94% for laser followed by ALA-PDT and 82% for ALA-PDT alone (P < .05).

Skin treated only with ALA-PDT developed minimal to moderate erythema that resolved within 5-7 days for all patients, but the laser-resurfaced skin developed “moderate to significant” erythema that resolved within 5-7 days with home care, she said.

Taken together, the results indicate that fractional CO₂ laser treatment yields safe and effective clearance of actinic keratoses with “ultra-short” incubation times, Dr. Alexiades-Armenakas said.

Deka manufactures the fractional CO₂ laser tested in the study, and DUSA Pharmaceuticals manufactures the blue light PDT device and the ALA product. Dr. Alexiades-Armenakas reported receiving clinical research grants from Deka, DUSA Pharmaceuticals, Alma, and Syneron.

KISSIMMEE, FLA. – Fractional carbon dioxide laser resurfacing followed by 30 minutes of aminolevulinic acid plus blue light photodynamic therapy cleared 94% of actinic keratoses, significantly more than ALA-PDT alone, according to the findings of a randomized, single-blinded, split-face study of 20 patients.

Laser resurfacing was associated with worse short-term erythema, but erythema resolved in about 7 days and was not associated with other adverse events, Dr. Macrene Alexiades-Armenakas said at the annual meeting of the American Society for Laser Medicine and Surgery.

Historically, two sessions of 20% topical ALA and blue light PDT have yielded actinic keratosis cure rates of 78% to 89%, but only with ALA incubation times of 14-18 hours, said Dr. Alexiades-Armenakas, associate clinical professor at Yale University, New Haven, Conn.

©Dr-Strangelove/ThinkStockPhotos.com

“Increasing drug penetration may serve to enhance PDT efficacy and shorten incubation time,” she said.

To test that hypothesis, she compared the safety and efficacy of 15- and 30-minute incubations of ALA and blue light PDT, with or without CO₂ laser resurfacing. After cleaning patients’ faces with acetone wipes and applying a topical anesthetic for 1 hour, she randomly selected one half of each patient’s face for pretreatment with fractional CO₂ laser, using settings of 15-28 W, 500 mcm dot spacing, and 600-800 microsecond dwell time.

Next, she applied 5-ALA to the entire face, then performed blue light illumination for 1,000 seconds. Half of the 20 patients were randomly assigned ALA incubation times of 15 minutes, while the other half underwent 30-minute incubations. She rechecked patients at 1 week, 4 weeks, and 8 weeks, and took digital photographs at baseline and at each recheck using identical lighting conditions. A blinded evaluator scored each side of each face, defining clearance as complete regression of actinic keratosis.

At 8 weeks, the rate of complete clearance for the 10 patients who underwent 15-minute ALA incubations was 88% for laser resurfacing followed by ALA-PDT, compared with 74% for ALA-PDT alone (P < .05), Dr. Alexiades-Armenakas reported. Clearance rates for the 30-minute incubation group were 94% for laser followed by ALA-PDT and 82% for ALA-PDT alone (P < .05).

Skin treated only with ALA-PDT developed minimal to moderate erythema that resolved within 5-7 days for all patients, but the laser-resurfaced skin developed “moderate to significant” erythema that resolved within 5-7 days with home care, she said.

Taken together, the results indicate that fractional CO₂ laser treatment yields safe and effective clearance of actinic keratoses with “ultra-short” incubation times, Dr. Alexiades-Armenakas said.

Deka manufactures the fractional CO₂ laser tested in the study, and DUSA Pharmaceuticals manufactures the blue light PDT device and the ALA product. Dr. Alexiades-Armenakas reported receiving clinical research grants from Deka, DUSA Pharmaceuticals, Alma, and Syneron.

KISSIMMEE, FLA. – Fractional carbon dioxide laser resurfacing followed by 30 minutes of aminolevulinic acid plus blue light photodynamic therapy cleared 94% of actinic keratoses, significantly more than ALA-PDT alone, according to the findings of a randomized, single-blinded, split-face study of 20 patients.

Laser resurfacing was associated with worse short-term erythema, but erythema resolved in about 7 days and was not associated with other adverse events, Dr. Macrene Alexiades-Armenakas said at the annual meeting of the American Society for Laser Medicine and Surgery.

Historically, two sessions of 20% topical ALA and blue light PDT have yielded actinic keratosis cure rates of 78% to 89%, but only with ALA incubation times of 14-18 hours, said Dr. Alexiades-Armenakas, associate clinical professor at Yale University, New Haven, Conn.

©Dr-Strangelove/ThinkStockPhotos.com

“Increasing drug penetration may serve to enhance PDT efficacy and shorten incubation time,” she said.

To test that hypothesis, she compared the safety and efficacy of 15- and 30-minute incubations of ALA and blue light PDT, with or without CO₂ laser resurfacing. After cleaning patients’ faces with acetone wipes and applying a topical anesthetic for 1 hour, she randomly selected one half of each patient’s face for pretreatment with fractional CO₂ laser, using settings of 15-28 W, 500 mcm dot spacing, and 600-800 microsecond dwell time.

Next, she applied 5-ALA to the entire face, then performed blue light illumination for 1,000 seconds. Half of the 20 patients were randomly assigned ALA incubation times of 15 minutes, while the other half underwent 30-minute incubations. She rechecked patients at 1 week, 4 weeks, and 8 weeks, and took digital photographs at baseline and at each recheck using identical lighting conditions. A blinded evaluator scored each side of each face, defining clearance as complete regression of actinic keratosis.

At 8 weeks, the rate of complete clearance for the 10 patients who underwent 15-minute ALA incubations was 88% for laser resurfacing followed by ALA-PDT, compared with 74% for ALA-PDT alone (P < .05), Dr. Alexiades-Armenakas reported. Clearance rates for the 30-minute incubation group were 94% for laser followed by ALA-PDT and 82% for ALA-PDT alone (P < .05).

Skin treated only with ALA-PDT developed minimal to moderate erythema that resolved within 5-7 days for all patients, but the laser-resurfaced skin developed “moderate to significant” erythema that resolved within 5-7 days with home care, she said.

Taken together, the results indicate that fractional CO₂ laser treatment yields safe and effective clearance of actinic keratoses with “ultra-short” incubation times, Dr. Alexiades-Armenakas said.

Deka manufactures the fractional CO₂ laser tested in the study, and DUSA Pharmaceuticals manufactures the blue light PDT device and the ALA product. Dr. Alexiades-Armenakas reported receiving clinical research grants from Deka, DUSA Pharmaceuticals, Alma, and Syneron.

PHILADELPHIA—Preclinical research suggests a cyclin-dependent kinase (CDK) inhibitor is active against acute leukemias, particularly those with mixed-lineage leukemia rearrangements (MLL-r).

CYC065 selectively inhibits CDK2, which drives cell-cycle transition and activates major DNA double-strand break repair pathways; CDK5, which drives metastatic spread; and CDK9, which regulates the transcription of genes important for the proliferation and survival of malignant cells.

Experiments have shown that CYC065 exhibits activity against acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), with and without MLL-r.

Daniella Zheleva, PhD, and her colleagues described these experiments in a poster at the AACR Annual Meeting 2015 (abstract 1650). All of the researchers are employees of Cyclacel Ltd., the company developing CYC065.

The researchers tested CYC065 in a panel of AML cell lines with wild-type MLL (HEL, HL60, Kasumi-1, KG-1, OCI-AML5, and PL21) and MLL-r (EOL-1, ML-2, MOLM-13, MV4-11, Nomo-1, OCI-AML2, and THP-1).

They found that MLL-r cell lines were “highly sensitive” to CYC065, but the sensitivity of cell lines with wild-type MLL correlated with the level of Bcl-2 family proteins. In the wild-type cell lines, IC_50/70/90 values were correlated with Bcl_XL and inversely correlated with Bak.

Six-hour pulse treatment of CYC065 at 0.5 µM to 1 µM was sufficient to cause 90% or greater cell death in sensitive cell lines. And cell lines with reduced sensitivity to the drug could be targeted by exposure to 10-hour pulse treatments of CYC065, or to CYC065 in combination with short pulses of Bcl-2 inhibitors.

The researchers observed “potent antitumor activity” when they administered CYC065 in AML xenograft models.

In an EOL-1 model, the median tumor growth inhibition on day 19 was 97% for mice that received CYC065 at 40 mg/kg (every day on days 1-5 and 8-12), 95% for mice that received CYC065 at 20 mg/kg every day on days 1-5 and 8-12), and 41% for mice that received cytarabine at 100 mg/kg (every day on days 1-5).

In the HL60 model, the median tumor growth inhibition on day 11 was 90% for mice that received CYC065 at 70 mg/kg (every day on days 1-5 and 8-12). And 2 mice achieved a complete response to treatment.

The researchers also found that CYC065 synergizes with cytarabine, particularly when CYC065 is given first. In fact, the combination could overcome the cytarabine resistance observed in the MV4-11 cell line.

CYC065 was “strongly synergistic” with Bcl2/Bcl_XL inhibitors as well, the researchers said. CYC065 synergized with ABT-199, ABT-263, and ABT-737 in both AML cell lines (THP-1 and HEL) and ALL cell lines (Jurkat and SEM).

The researchers said the potent in vitro and in vivo activity of CYC065 and the ability to combine the drug with other antileukemic agents suggest that it may have therapeutic potential in AML and ALL.

PHILADELPHIA—Preclinical research suggests a cyclin-dependent kinase (CDK) inhibitor is active against acute leukemias, particularly those with mixed-lineage leukemia rearrangements (MLL-r).

CYC065 selectively inhibits CDK2, which drives cell-cycle transition and activates major DNA double-strand break repair pathways; CDK5, which drives metastatic spread; and CDK9, which regulates the transcription of genes important for the proliferation and survival of malignant cells.

Experiments have shown that CYC065 exhibits activity against acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), with and without MLL-r.

Daniella Zheleva, PhD, and her colleagues described these experiments in a poster at the AACR Annual Meeting 2015 (abstract 1650). All of the researchers are employees of Cyclacel Ltd., the company developing CYC065.

The researchers tested CYC065 in a panel of AML cell lines with wild-type MLL (HEL, HL60, Kasumi-1, KG-1, OCI-AML5, and PL21) and MLL-r (EOL-1, ML-2, MOLM-13, MV4-11, Nomo-1, OCI-AML2, and THP-1).

They found that MLL-r cell lines were “highly sensitive” to CYC065, but the sensitivity of cell lines with wild-type MLL correlated with the level of Bcl-2 family proteins. In the wild-type cell lines, IC_50/70/90 values were correlated with Bcl_XL and inversely correlated with Bak.

Six-hour pulse treatment of CYC065 at 0.5 µM to 1 µM was sufficient to cause 90% or greater cell death in sensitive cell lines. And cell lines with reduced sensitivity to the drug could be targeted by exposure to 10-hour pulse treatments of CYC065, or to CYC065 in combination with short pulses of Bcl-2 inhibitors.

The researchers observed “potent antitumor activity” when they administered CYC065 in AML xenograft models.

In an EOL-1 model, the median tumor growth inhibition on day 19 was 97% for mice that received CYC065 at 40 mg/kg (every day on days 1-5 and 8-12), 95% for mice that received CYC065 at 20 mg/kg every day on days 1-5 and 8-12), and 41% for mice that received cytarabine at 100 mg/kg (every day on days 1-5).

In the HL60 model, the median tumor growth inhibition on day 11 was 90% for mice that received CYC065 at 70 mg/kg (every day on days 1-5 and 8-12). And 2 mice achieved a complete response to treatment.

The researchers also found that CYC065 synergizes with cytarabine, particularly when CYC065 is given first. In fact, the combination could overcome the cytarabine resistance observed in the MV4-11 cell line.

CYC065 was “strongly synergistic” with Bcl2/Bcl_XL inhibitors as well, the researchers said. CYC065 synergized with ABT-199, ABT-263, and ABT-737 in both AML cell lines (THP-1 and HEL) and ALL cell lines (Jurkat and SEM).

The researchers said the potent in vitro and in vivo activity of CYC065 and the ability to combine the drug with other antileukemic agents suggest that it may have therapeutic potential in AML and ALL.

PHILADELPHIA—Preclinical research suggests a cyclin-dependent kinase (CDK) inhibitor is active against acute leukemias, particularly those with mixed-lineage leukemia rearrangements (MLL-r).

CYC065 selectively inhibits CDK2, which drives cell-cycle transition and activates major DNA double-strand break repair pathways; CDK5, which drives metastatic spread; and CDK9, which regulates the transcription of genes important for the proliferation and survival of malignant cells.

Experiments have shown that CYC065 exhibits activity against acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), with and without MLL-r.

Daniella Zheleva, PhD, and her colleagues described these experiments in a poster at the AACR Annual Meeting 2015 (abstract 1650). All of the researchers are employees of Cyclacel Ltd., the company developing CYC065.

The researchers tested CYC065 in a panel of AML cell lines with wild-type MLL (HEL, HL60, Kasumi-1, KG-1, OCI-AML5, and PL21) and MLL-r (EOL-1, ML-2, MOLM-13, MV4-11, Nomo-1, OCI-AML2, and THP-1).

They found that MLL-r cell lines were “highly sensitive” to CYC065, but the sensitivity of cell lines with wild-type MLL correlated with the level of Bcl-2 family proteins. In the wild-type cell lines, IC_50/70/90 values were correlated with Bcl_XL and inversely correlated with Bak.

Six-hour pulse treatment of CYC065 at 0.5 µM to 1 µM was sufficient to cause 90% or greater cell death in sensitive cell lines. And cell lines with reduced sensitivity to the drug could be targeted by exposure to 10-hour pulse treatments of CYC065, or to CYC065 in combination with short pulses of Bcl-2 inhibitors.

The researchers observed “potent antitumor activity” when they administered CYC065 in AML xenograft models.

In an EOL-1 model, the median tumor growth inhibition on day 19 was 97% for mice that received CYC065 at 40 mg/kg (every day on days 1-5 and 8-12), 95% for mice that received CYC065 at 20 mg/kg every day on days 1-5 and 8-12), and 41% for mice that received cytarabine at 100 mg/kg (every day on days 1-5).

In the HL60 model, the median tumor growth inhibition on day 11 was 90% for mice that received CYC065 at 70 mg/kg (every day on days 1-5 and 8-12). And 2 mice achieved a complete response to treatment.

The researchers also found that CYC065 synergizes with cytarabine, particularly when CYC065 is given first. In fact, the combination could overcome the cytarabine resistance observed in the MV4-11 cell line.

CYC065 was “strongly synergistic” with Bcl2/Bcl_XL inhibitors as well, the researchers said. CYC065 synergized with ABT-199, ABT-263, and ABT-737 in both AML cell lines (THP-1 and HEL) and ALL cell lines (Jurkat and SEM).

The researchers said the potent in vitro and in vivo activity of CYC065 and the ability to combine the drug with other antileukemic agents suggest that it may have therapeutic potential in AML and ALL.

Attendees at AACR 2015

PHILADELPHIA—A drug that has fallen short of expectations in clinical trials of prostate cancer may be effective for treating multiple myeloma (MM), according to research presented at the AACR Annual Meeting 2015.

The drug, tasquinimod, inhibits the function of S100A9, a pro-inflammatory protein that is elevated in MM, prostate cancer, and other malignancies.

Researchers found that tasquinimod can reduce tumor growth and improve survival in mouse models of MM. And these effects are associated with reduced angiogenesis in the bone marrow.

Cindy Lin, PhD, of the Wistar Institute in Philadelphia, Pennsylvania, and her colleagues presented these findings as abstract 1364.* The research was supported by Active Biotech and Ipsen, the companies developing tasquinimod.

Dr Lin noted that tasquinimod has already been tested in clinical trials of prostate cancer and initially appeared to be very effective. However, recent results from a phase 3 trial suggested the drug does not confer a favorable risk-benefit ratio for this population.

So Active Biotech and Ipsen decided to discontinue all trials of tasquinimod in prostate cancer. But the preclinical results observed in MM suggest tasquinimod may hold promise for treating these patients.

Activity in MM

Dr Lin said previous preclinical experiments revealed that myeloid-derived suppressor cells are involved in regulating MM progression, and these cells produce S100A9.

Tasquinimod is a quinoline-3-carboxamide derivative that binds to S100A9 and inhibits interaction with its receptors. So Dr Lin and her colleagues decided to investigate the antitumor effect of the drug in mouse models of MM.

The researchers initially tested tasquinimod in a syngeneic MM model, randomizing mice to treatment or control. Mice in the treatment group received tasquinimod at 30 mg/kg/day in their drinking water for 28 days.

Tasquinimod significantly improved survival in this model (P<0.005). All control mice died within 30 days of tumor inoculation, but about 40% of tasquinimod-treated mice were still alive more than 80 days out.

The researchers then tested tasquinimod in xenograft models of human MM. The drug significantly reduced tumor size in both H929 (P=0.0042) and RPMI-8226 models (P=0.0003). Treatment significantly improved survival in the H929 (P=0.0008) and RPMI-8226 models as well (P=0.0243).

Dr Lin said she and her colleagues did not see any side effects of treatment in any of the mice.

Investigating the mechanism

To determine if the antitumor effect of tasquinimod is, in fact, mediated through inhibition of S100A9, the researchers administered the drug to S100A9-knockout mice with MM. Tasquinimod did not improve survival in these mice, which suggests its anti-MM effects are mediated through S100A9 inhibition.

“To try and investigate some of the mechanisms of how survival is improved in tasquinimod-treated, tumor-bearing mice, we looked at a variety of different things, including angiogenesis,” Dr Lin said.

“We used CD31 immunohistochemistry to look at angiogenesis, and, in the untreated mice, we didn’t see a lot of staining. But in the tumor-bearing mice, there was a lot more staining [P=0.0231]. And when we gave the mice tasquinimod, angiogenesis was significantly decreased [P<0.0001].”

The researchers also looked at different angiogenic factors. And they found that, compared to control-treated mice with MM, tumor-bearing mice that received tasquinimod had a significant decrease in serum levels of VEGF, FGF2, tissue factor, and endoglin.

The team is now assessing the effects of S100A9 and tasquinimod on megakaryocytes and platelets, 2 of the major cell populations that promote angiogenesis.

*Information in the abstract differs from that presented at the meeting.

Attendees at AACR 2015

PHILADELPHIA—A drug that has fallen short of expectations in clinical trials of prostate cancer may be effective for treating multiple myeloma (MM), according to research presented at the AACR Annual Meeting 2015.

The drug, tasquinimod, inhibits the function of S100A9, a pro-inflammatory protein that is elevated in MM, prostate cancer, and other malignancies.

Researchers found that tasquinimod can reduce tumor growth and improve survival in mouse models of MM. And these effects are associated with reduced angiogenesis in the bone marrow.

Cindy Lin, PhD, of the Wistar Institute in Philadelphia, Pennsylvania, and her colleagues presented these findings as abstract 1364.* The research was supported by Active Biotech and Ipsen, the companies developing tasquinimod.

Dr Lin noted that tasquinimod has already been tested in clinical trials of prostate cancer and initially appeared to be very effective. However, recent results from a phase 3 trial suggested the drug does not confer a favorable risk-benefit ratio for this population.

So Active Biotech and Ipsen decided to discontinue all trials of tasquinimod in prostate cancer. But the preclinical results observed in MM suggest tasquinimod may hold promise for treating these patients.

Activity in MM

Dr Lin said previous preclinical experiments revealed that myeloid-derived suppressor cells are involved in regulating MM progression, and these cells produce S100A9.

Tasquinimod is a quinoline-3-carboxamide derivative that binds to S100A9 and inhibits interaction with its receptors. So Dr Lin and her colleagues decided to investigate the antitumor effect of the drug in mouse models of MM.

The researchers initially tested tasquinimod in a syngeneic MM model, randomizing mice to treatment or control. Mice in the treatment group received tasquinimod at 30 mg/kg/day in their drinking water for 28 days.

Tasquinimod significantly improved survival in this model (P<0.005). All control mice died within 30 days of tumor inoculation, but about 40% of tasquinimod-treated mice were still alive more than 80 days out.

The researchers then tested tasquinimod in xenograft models of human MM. The drug significantly reduced tumor size in both H929 (P=0.0042) and RPMI-8226 models (P=0.0003). Treatment significantly improved survival in the H929 (P=0.0008) and RPMI-8226 models as well (P=0.0243).

Dr Lin said she and her colleagues did not see any side effects of treatment in any of the mice.

Investigating the mechanism

To determine if the antitumor effect of tasquinimod is, in fact, mediated through inhibition of S100A9, the researchers administered the drug to S100A9-knockout mice with MM. Tasquinimod did not improve survival in these mice, which suggests its anti-MM effects are mediated through S100A9 inhibition.

“To try and investigate some of the mechanisms of how survival is improved in tasquinimod-treated, tumor-bearing mice, we looked at a variety of different things, including angiogenesis,” Dr Lin said.

“We used CD31 immunohistochemistry to look at angiogenesis, and, in the untreated mice, we didn’t see a lot of staining. But in the tumor-bearing mice, there was a lot more staining [P=0.0231]. And when we gave the mice tasquinimod, angiogenesis was significantly decreased [P<0.0001].”

The researchers also looked at different angiogenic factors. And they found that, compared to control-treated mice with MM, tumor-bearing mice that received tasquinimod had a significant decrease in serum levels of VEGF, FGF2, tissue factor, and endoglin.

The team is now assessing the effects of S100A9 and tasquinimod on megakaryocytes and platelets, 2 of the major cell populations that promote angiogenesis.

*Information in the abstract differs from that presented at the meeting.

Attendees at AACR 2015

PHILADELPHIA—A drug that has fallen short of expectations in clinical trials of prostate cancer may be effective for treating multiple myeloma (MM), according to research presented at the AACR Annual Meeting 2015.

The drug, tasquinimod, inhibits the function of S100A9, a pro-inflammatory protein that is elevated in MM, prostate cancer, and other malignancies.

Researchers found that tasquinimod can reduce tumor growth and improve survival in mouse models of MM. And these effects are associated with reduced angiogenesis in the bone marrow.

Cindy Lin, PhD, of the Wistar Institute in Philadelphia, Pennsylvania, and her colleagues presented these findings as abstract 1364.* The research was supported by Active Biotech and Ipsen, the companies developing tasquinimod.

Dr Lin noted that tasquinimod has already been tested in clinical trials of prostate cancer and initially appeared to be very effective. However, recent results from a phase 3 trial suggested the drug does not confer a favorable risk-benefit ratio for this population.

So Active Biotech and Ipsen decided to discontinue all trials of tasquinimod in prostate cancer. But the preclinical results observed in MM suggest tasquinimod may hold promise for treating these patients.

Activity in MM

Dr Lin said previous preclinical experiments revealed that myeloid-derived suppressor cells are involved in regulating MM progression, and these cells produce S100A9.

Tasquinimod is a quinoline-3-carboxamide derivative that binds to S100A9 and inhibits interaction with its receptors. So Dr Lin and her colleagues decided to investigate the antitumor effect of the drug in mouse models of MM.

The researchers initially tested tasquinimod in a syngeneic MM model, randomizing mice to treatment or control. Mice in the treatment group received tasquinimod at 30 mg/kg/day in their drinking water for 28 days.

Tasquinimod significantly improved survival in this model (P<0.005). All control mice died within 30 days of tumor inoculation, but about 40% of tasquinimod-treated mice were still alive more than 80 days out.

The researchers then tested tasquinimod in xenograft models of human MM. The drug significantly reduced tumor size in both H929 (P=0.0042) and RPMI-8226 models (P=0.0003). Treatment significantly improved survival in the H929 (P=0.0008) and RPMI-8226 models as well (P=0.0243).

Dr Lin said she and her colleagues did not see any side effects of treatment in any of the mice.

Investigating the mechanism

To determine if the antitumor effect of tasquinimod is, in fact, mediated through inhibition of S100A9, the researchers administered the drug to S100A9-knockout mice with MM. Tasquinimod did not improve survival in these mice, which suggests its anti-MM effects are mediated through S100A9 inhibition.

“To try and investigate some of the mechanisms of how survival is improved in tasquinimod-treated, tumor-bearing mice, we looked at a variety of different things, including angiogenesis,” Dr Lin said.

“We used CD31 immunohistochemistry to look at angiogenesis, and, in the untreated mice, we didn’t see a lot of staining. But in the tumor-bearing mice, there was a lot more staining [P=0.0231]. And when we gave the mice tasquinimod, angiogenesis was significantly decreased [P<0.0001].”

The researchers also looked at different angiogenic factors. And they found that, compared to control-treated mice with MM, tumor-bearing mice that received tasquinimod had a significant decrease in serum levels of VEGF, FGF2, tissue factor, and endoglin.

The team is now assessing the effects of S100A9 and tasquinimod on megakaryocytes and platelets, 2 of the major cell populations that promote angiogenesis.

*Information in the abstract differs from that presented at the meeting.

One of the key indicators of a nation’s health is how well it can care for its young. Despite many advances in medical care and improvements in access to care, infant mortality remains a significant concern worldwide. According to the World Health Organization, the leading cause of death among children under age 5 is preterm birth complications. With an estimated 15 million babies born prematurely (prior to 37 weeks’ gestation) globally each year, it is vital for ob.gyns. to uncover ways to predict, diagnose early, and treat the causes of preterm birth.

While the challenges to infant health could be considered more of an issue in developing countries, here in the United States, the Centers for Disease Control and Prevention estimates that 1 in 9 babies is born prematurely. Preterm birth-related causes of death (i.e., breathing and feeding problems and disabilities) accounted for 35% of all infant deaths in 2010.

The World Health Organization (WHO) lists the United States as one of the top 10 countries with the greatest number of preterm births, despite the fact that we spend approximately 17.1% of our gross domestic product in total health care expenditures – the highest rate among our peer nations.

In the April 2014 edition of Master Class, we discussed one of the primary causes of preterm birth, bacterial infections, and specifically the need for ob.gyns. to rigorously screen patients for asymptomatic bacteriuria, which can lead to pyelonephritis. This month, we examine another biologic marker of preterm birth, cervical length.

Seminal studies of transvaginal sonography to measure cervical length during pregnancy and predict premature birth were published more than 2 decades ago. This work showed that a short cervix at 24 and 28 weeks’ gestation predicted preterm birth. Since then, clinical studies have demonstrated the utility of cervical length screening in women with prior preterm pregnancies. In the last decade, three large, randomized human trials have examined the usefulness of universal cervical length screening (Am. J. Obstet. Gynecol. 2012;207:101-6). However, the results of these trials have given practitioners a confusing picture of the predictability of this biologic marker.

Given the complexity of the “to screen or not to screen” issue, we have devoted this Master Class to a discussion on the role of cervical length screening and the prediction of preterm birth. Our guest author this month is Dr. Erika Werner, an assistant professor in ob.gyn (maternal-fetal medicine) in the department of obstetrics and gynecology at Brown University, in Providence, R.I., and an expert in the area of preterm birth.

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].

One of the key indicators of a nation’s health is how well it can care for its young. Despite many advances in medical care and improvements in access to care, infant mortality remains a significant concern worldwide. According to the World Health Organization, the leading cause of death among children under age 5 is preterm birth complications. With an estimated 15 million babies born prematurely (prior to 37 weeks’ gestation) globally each year, it is vital for ob.gyns. to uncover ways to predict, diagnose early, and treat the causes of preterm birth.

While the challenges to infant health could be considered more of an issue in developing countries, here in the United States, the Centers for Disease Control and Prevention estimates that 1 in 9 babies is born prematurely. Preterm birth-related causes of death (i.e., breathing and feeding problems and disabilities) accounted for 35% of all infant deaths in 2010.

The World Health Organization (WHO) lists the United States as one of the top 10 countries with the greatest number of preterm births, despite the fact that we spend approximately 17.1% of our gross domestic product in total health care expenditures – the highest rate among our peer nations.

In the April 2014 edition of Master Class, we discussed one of the primary causes of preterm birth, bacterial infections, and specifically the need for ob.gyns. to rigorously screen patients for asymptomatic bacteriuria, which can lead to pyelonephritis. This month, we examine another biologic marker of preterm birth, cervical length.

Seminal studies of transvaginal sonography to measure cervical length during pregnancy and predict premature birth were published more than 2 decades ago. This work showed that a short cervix at 24 and 28 weeks’ gestation predicted preterm birth. Since then, clinical studies have demonstrated the utility of cervical length screening in women with prior preterm pregnancies. In the last decade, three large, randomized human trials have examined the usefulness of universal cervical length screening (Am. J. Obstet. Gynecol. 2012;207:101-6). However, the results of these trials have given practitioners a confusing picture of the predictability of this biologic marker.

Given the complexity of the “to screen or not to screen” issue, we have devoted this Master Class to a discussion on the role of cervical length screening and the prediction of preterm birth. Our guest author this month is Dr. Erika Werner, an assistant professor in ob.gyn (maternal-fetal medicine) in the department of obstetrics and gynecology at Brown University, in Providence, R.I., and an expert in the area of preterm birth.

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].

One of the key indicators of a nation’s health is how well it can care for its young. Despite many advances in medical care and improvements in access to care, infant mortality remains a significant concern worldwide. According to the World Health Organization, the leading cause of death among children under age 5 is preterm birth complications. With an estimated 15 million babies born prematurely (prior to 37 weeks’ gestation) globally each year, it is vital for ob.gyns. to uncover ways to predict, diagnose early, and treat the causes of preterm birth.

While the challenges to infant health could be considered more of an issue in developing countries, here in the United States, the Centers for Disease Control and Prevention estimates that 1 in 9 babies is born prematurely. Preterm birth-related causes of death (i.e., breathing and feeding problems and disabilities) accounted for 35% of all infant deaths in 2010.

The World Health Organization (WHO) lists the United States as one of the top 10 countries with the greatest number of preterm births, despite the fact that we spend approximately 17.1% of our gross domestic product in total health care expenditures – the highest rate among our peer nations.

In the April 2014 edition of Master Class, we discussed one of the primary causes of preterm birth, bacterial infections, and specifically the need for ob.gyns. to rigorously screen patients for asymptomatic bacteriuria, which can lead to pyelonephritis. This month, we examine another biologic marker of preterm birth, cervical length.

Seminal studies of transvaginal sonography to measure cervical length during pregnancy and predict premature birth were published more than 2 decades ago. This work showed that a short cervix at 24 and 28 weeks’ gestation predicted preterm birth. Since then, clinical studies have demonstrated the utility of cervical length screening in women with prior preterm pregnancies. In the last decade, three large, randomized human trials have examined the usefulness of universal cervical length screening (Am. J. Obstet. Gynecol. 2012;207:101-6). However, the results of these trials have given practitioners a confusing picture of the predictability of this biologic marker.

Given the complexity of the “to screen or not to screen” issue, we have devoted this Master Class to a discussion on the role of cervical length screening and the prediction of preterm birth. Our guest author this month is Dr. Erika Werner, an assistant professor in ob.gyn (maternal-fetal medicine) in the department of obstetrics and gynecology at Brown University, in Providence, R.I., and an expert in the area of preterm birth.

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].

Rates of preterm birth in the United States have been falling since 2006, but the rates of early preterm birth in singletons (those under 34 weeks’ gestation), specifically, have not trended downward as dramatically as have late preterm birth in singletons (34-36 weeks). According to 2015 data from the National Vital Statistics Reports, the rate of early preterm births is still 3.4% in all pregnancies and 2.7% among singletons.

While the number of neonates born before 37 weeks of gestation remains high – approximately 11% in 2013 – and signifies a continuing public health problem, the rate of early preterm birth is particularly concerning because early preterm birth is more significantly associated with neonatal mortality, long-term morbidity and extended neonatal intensive care unit stays, all leading to increased health care expenditures.

Finding predictors for preterm birth that are stronger than traditional clinical factors has long been a goal of ob.gyns. because the vast majority of all spontaneous preterm births occur to women without known risk factors (i.e., multiple gestations or prior preterm birth).

Cervical length in the midtrimester is now a well-verified predictor of preterm birth, for both low- and high-risk women. Furthermore, vaginal progesterone has been shown to be a safe and beneficial intervention for women with no known risk factors who are diagnosed with a shortened cervical length (< 2 cm), and cervical cerclage has been suggested to reduce the risk of preterm birth for women with a history of prior preterm birth who also have a shortened cervical length.

Some are now advocating universal cervical length screening for women with singleton gestations, but before universal screening is mandated, the downstream effect of such a change in practice must be considered.

Backdrop to screening

Cervical length measurement was first investigated more than 25 years ago as a possible predictor of preterm birth. In 1996, a prospective multicenter study of almost 3,000 women with singleton pregnancies showed that the risk of preterm delivery is inversely and directly related to the length of the cervix, as measured with vaginal ultrasonography (N. Engl. J. Med. 1996;334:567-72).

In fact, at 24 weeks’ gestation, every 1 mm of additional cervical length equates to a significant decrease in preterm birth risk (odds ratio, 0.91). Several other studies, in addition to the landmark 1996 study, have similarly demonstrated this inverse relationship between preterm birth risk and cervical length between 18 and 24 weeks’ gestation.

However, the use of cervical measurement did not achieve widespread use until more than a decade later, when researchers began to identify interventions that could prolong pregnancy if a short cervix was diagnosed in the second trimester.

For example, Dr. E.B. Fonseca’s study of almost 25,000 asymptomatic pregnant women, demonstrated that daily vaginal progesterone reduced the risk of spontaneous delivery before 34 weeks by approximately 44% in women identified with a cervical length of 1.5 cm or less (N. Engl. J. Med. 2007;357:462-9). The vast majority of the women in this study had singleton pregnancies.

Shortly thereafter, Dr. S.S. Hassan and her colleagues completed a similar trial in women with singleton gestations and transvaginal cervical lengths between 1.0 and 2.0 cm at 20-23 weeks’ gestation. In this trial, nightly progesterone gel (with 90 mg progesterone per application) was associated with a 45% reduction in preterm birth before 33 weeks and a 38% reduction in preterm birth before 35 weeks (Ultrasound. Obstet. Gynecol. 2011;38:18-31).

A meta-analysis led by Dr. Roberto Romero, which included the Fonseca and Hassan trials, looked specifically at 775 women with a midtrimester cervical length of 2.5 cm or less. Women with a singleton gestation who had no history of preterm birth had a 40% reduction in the rate of early preterm birth when they were treated with vaginal progesterone (Am. J. Obstet. Gynecol. 2012;206:124-e1-19).

The benefits of identifying a short cervix likely extend to women with a history of prior preterm birth. A patient-level meta-analysis published in 2011 demonstrated that cervical cerclage placement was associated with a significant reduction in preterm birth before 35 weeks’ gestation in women with singleton gestations, previous spontaneous preterm birth, and cervical length less than 2.5 cm before 24 weeks’ gestation (Obstet. Gynecol. 2011;117:663-71).

The possible benefits of diagnosing and intervening for a shortened cervix have tipped many experts and clinicians toward the practice of universal cervical length screening of all singleton pregnancies. Research has shown that we can accurately obtain a cervical-length measurement before 24 weeks, and that we have effective and safe interventions for cases of short cervix: cerclage in women with a history of preterm birth who are already receiving progesterone, and vaginal progesterone in women without such a history.

 

Screening certainties and doubts

In 2011, my colleagues and I compared the cost effectiveness of two approaches to preterm birth prevention in low-risk pregnancies: no screening versus a single transvaginal ultrasound cervical-length measurement in all asymptomatic, low-risk singleton pregnant individuals between 18 and 24 weeks’ gestation.

In our model, women identified as having a cervical length less than 1.5 cm would be offered vaginal progesterone. Based on published data, we assumed there would be a 92% adherence rate, and a 45% reduction in deliveries before 34 weeks with progesterone treatment.

We found that in low-risk pregnancies, universal transvaginal cervical-length ultrasound screening and progesterone intervention would be cost effective and in many cases cost saving. We estimated that screening would prevent 248 early preterm births – as well as 22 neonatal deaths or neonates with long-term neurologic deficits – per 100,000 deliveries.

Our sensitivity analyses showed that screening remained cost saving under a range of clinical scenarios, including varied preterm birth rates and predictive values of a shortened cervix. Screening was not cost saving, but remained cost effective, when the expense of a transvaginal ultrasound scan exceeds $187 or when vaginal progesterone is assumed to reduce the risk of early preterm delivery by less than 20% (Ultrasound Obstet. Gynecol. 2011;38;32-37).

Neither the American College of Obstetricians and Gynecologists nor the Society for Maternal-Fetal Medicine support mandated universal transvaginal ultrasound cervical length screening. Both organizations state, however, that the approach may be considered in women with singleton gestations without prior spontaneous preterm birth.

Interestingly, Thomas Jefferson University in Philadelphia, which uses a universal screening program for singleton gestations without prior preterm birth, has recently published data that complicate the growing trend toward universal cervical length screening.

The Philadelphia clinicians followed a strategy whereby women with a transvaginal cervical length of 2 cm or less were prescribed vaginal progesterone (90 mg vaginal progesterone gel, or 200 mg micronized progesterone gel capsules). Those with a cervical length between approximately 2 cm and 2.5 cm were asked to return for a follow-up cervical length measurement before 24 weeks’ gestation.

What they found in this cohort was surprising: a rate of short cervix that is significantly lower than what previous research has shown.

Among those screened, 0.8% of women had a cervical length of 2 cm or less on an initial transvaginal ultrasonogram. Previously, a prevalence of 1%-2% for an even shorter cervical length (less than 1.5 cm) was fairly consistent in the literature.

As Dr. Kelly M. Orzechowski and her colleagues point out, the low incidence of short cervix “raises questions regarding whether universal transvaginal ultrasonogram cervical length screening in low-risk asymptomatic women is beneficial” (Obstet. Gynecol. 2014;124:520-5).

In our 2011 cost-effectiveness analysis, we found that screening was no longer a cost-saving practice when the incidence of cervical length less than 1.5 cm falls below 0.8%. Screening remained cost effective, however.

Recently, we found that if the Philadelphia protocol is followed and the U.S. population has an incidence of shortened cervix similar to that described by Dr. Orzechowski and her colleagues, universal cervical length screening in low-risk singleton pregnancies is cost effective but not cost saving. Furthermore, we found several additional plausible situations in this unpublished analysis in which universal screening ceased to be cost effective.

Thus, before we move to a strategy of mandated universal screening, we need better population-based estimates of the incidence of short cervix in a truly low-risk population.

We also must consider the future costs of progesterone. It is possible that costs may increase significantly if vaginal progesterone wins approval from the Food and Drug Administration for this indication.

Finally, if universal cervical length screening is to become the standard of care, we need policies in place to prevent misuse of the screening technology that would inevitably drive up costs without improving outcomes. For example, we must ensure that one cervical length measurement does not transition into serial cervical length measurements over the course of pregnancy, since measurement after 24 weeks has limited clinical utility. Similarly, progesterone use for a cervical length less than or equal to 2.0 cm cannot progress to progesterone for anyone approaching 2.0 cm (i.e. 2.5 cm or even 3 cm) as there is no evidence to suggest a benefit for women with longer cervixes.

Over time, it would be beneficial to have additional data on how best to manage patients who have a cervical length of 2 cm-2.5 cm before 24 weeks’ gestation. Many of us ask these women to return for a follow-up measurement and some may prescribe progesterone. However, we lack evidence for either approach; while a cervical length measurement less than 2.5 cm is clearly associated with an increased risk of preterm birth, the benefit of treatment has been demonstrated only with a cervical length of 2 cm or less.

 

Today and the future

For women with a history of preterm birth, cervical length screening is now routine. For low-risk pregnant women – those without a history of previous spontaneous preterm delivery – various approaches are currently taken. Most physicians recommend assessing the cervical length transabdominally at the time of the 18-20-week ultrasound, and proceeding to transvaginal ultrasonography if the cervical length is less than 3 cm or 3.5 cm.

To reliably image the cervix with transabdominal ultrasound, it should be performed with a full bladder and with the understanding that the cervix appears longer (6 mm longer, on average) when the bladder is full (Aust. N. Z. J. Obstet. Gynaecol. 2014;54:250-55).

Transvaginal ultrasound has been widely recognized as a sensitive and reproducible method for detecting shortened cervical length. Overall, this tool has several advantages over the transabdominal approach. However, the lack of universal access to transvaginal ultrasound and to consistently reliable cervical length measurements have been valid concerns of those who oppose universal transvaginal ultrasound cervical length screening.

Such concerns likely will lessen over time as transvaginal ultrasound continues to become more pervasive. Several years ago, the Perinatal Quality Foundation set standards for measuring the cervix and launched the Cervical Length Education and Review (CLEAR) program. When sonographers and physicians obtain training and credentialing, there appears to be only a 5%-10% intraobserver variability in cervical length measurement. (The PQF’s initial focus in 2005 was the Nuchal Translucency Quality Review program.)

Increasingly, I believe, transvaginal ultrasound cervical length measurement will be utilized to identify women at high risk for early preterm birth so that low-risk women can receive progesterone and high-risk women (those with a history of preterm birth) can be considered as candidates for cerclage placement. In the process, the quality of clinical care as well as the quality of our research data will improve. Whether and when such screening will become universal, however, is still uncertain.

Dr. Werner reported that she has no financial disclosures relevant to this Master Class.

Rates of preterm birth in the United States have been falling since 2006, but the rates of early preterm birth in singletons (those under 34 weeks’ gestation), specifically, have not trended downward as dramatically as have late preterm birth in singletons (34-36 weeks). According to 2015 data from the National Vital Statistics Reports, the rate of early preterm births is still 3.4% in all pregnancies and 2.7% among singletons.

While the number of neonates born before 37 weeks of gestation remains high – approximately 11% in 2013 – and signifies a continuing public health problem, the rate of early preterm birth is particularly concerning because early preterm birth is more significantly associated with neonatal mortality, long-term morbidity and extended neonatal intensive care unit stays, all leading to increased health care expenditures.

Finding predictors for preterm birth that are stronger than traditional clinical factors has long been a goal of ob.gyns. because the vast majority of all spontaneous preterm births occur to women without known risk factors (i.e., multiple gestations or prior preterm birth).

Cervical length in the midtrimester is now a well-verified predictor of preterm birth, for both low- and high-risk women. Furthermore, vaginal progesterone has been shown to be a safe and beneficial intervention for women with no known risk factors who are diagnosed with a shortened cervical length (< 2 cm), and cervical cerclage has been suggested to reduce the risk of preterm birth for women with a history of prior preterm birth who also have a shortened cervical length.

Some are now advocating universal cervical length screening for women with singleton gestations, but before universal screening is mandated, the downstream effect of such a change in practice must be considered.

Backdrop to screening

Cervical length measurement was first investigated more than 25 years ago as a possible predictor of preterm birth. In 1996, a prospective multicenter study of almost 3,000 women with singleton pregnancies showed that the risk of preterm delivery is inversely and directly related to the length of the cervix, as measured with vaginal ultrasonography (N. Engl. J. Med. 1996;334:567-72).

In fact, at 24 weeks’ gestation, every 1 mm of additional cervical length equates to a significant decrease in preterm birth risk (odds ratio, 0.91). Several other studies, in addition to the landmark 1996 study, have similarly demonstrated this inverse relationship between preterm birth risk and cervical length between 18 and 24 weeks’ gestation.

However, the use of cervical measurement did not achieve widespread use until more than a decade later, when researchers began to identify interventions that could prolong pregnancy if a short cervix was diagnosed in the second trimester.

For example, Dr. E.B. Fonseca’s study of almost 25,000 asymptomatic pregnant women, demonstrated that daily vaginal progesterone reduced the risk of spontaneous delivery before 34 weeks by approximately 44% in women identified with a cervical length of 1.5 cm or less (N. Engl. J. Med. 2007;357:462-9). The vast majority of the women in this study had singleton pregnancies.

Shortly thereafter, Dr. S.S. Hassan and her colleagues completed a similar trial in women with singleton gestations and transvaginal cervical lengths between 1.0 and 2.0 cm at 20-23 weeks’ gestation. In this trial, nightly progesterone gel (with 90 mg progesterone per application) was associated with a 45% reduction in preterm birth before 33 weeks and a 38% reduction in preterm birth before 35 weeks (Ultrasound. Obstet. Gynecol. 2011;38:18-31).

A meta-analysis led by Dr. Roberto Romero, which included the Fonseca and Hassan trials, looked specifically at 775 women with a midtrimester cervical length of 2.5 cm or less. Women with a singleton gestation who had no history of preterm birth had a 40% reduction in the rate of early preterm birth when they were treated with vaginal progesterone (Am. J. Obstet. Gynecol. 2012;206:124-e1-19).

The benefits of identifying a short cervix likely extend to women with a history of prior preterm birth. A patient-level meta-analysis published in 2011 demonstrated that cervical cerclage placement was associated with a significant reduction in preterm birth before 35 weeks’ gestation in women with singleton gestations, previous spontaneous preterm birth, and cervical length less than 2.5 cm before 24 weeks’ gestation (Obstet. Gynecol. 2011;117:663-71).

The possible benefits of diagnosing and intervening for a shortened cervix have tipped many experts and clinicians toward the practice of universal cervical length screening of all singleton pregnancies. Research has shown that we can accurately obtain a cervical-length measurement before 24 weeks, and that we have effective and safe interventions for cases of short cervix: cerclage in women with a history of preterm birth who are already receiving progesterone, and vaginal progesterone in women without such a history.

 

Screening certainties and doubts

In 2011, my colleagues and I compared the cost effectiveness of two approaches to preterm birth prevention in low-risk pregnancies: no screening versus a single transvaginal ultrasound cervical-length measurement in all asymptomatic, low-risk singleton pregnant individuals between 18 and 24 weeks’ gestation.

In our model, women identified as having a cervical length less than 1.5 cm would be offered vaginal progesterone. Based on published data, we assumed there would be a 92% adherence rate, and a 45% reduction in deliveries before 34 weeks with progesterone treatment.

We found that in low-risk pregnancies, universal transvaginal cervical-length ultrasound screening and progesterone intervention would be cost effective and in many cases cost saving. We estimated that screening would prevent 248 early preterm births – as well as 22 neonatal deaths or neonates with long-term neurologic deficits – per 100,000 deliveries.

Our sensitivity analyses showed that screening remained cost saving under a range of clinical scenarios, including varied preterm birth rates and predictive values of a shortened cervix. Screening was not cost saving, but remained cost effective, when the expense of a transvaginal ultrasound scan exceeds $187 or when vaginal progesterone is assumed to reduce the risk of early preterm delivery by less than 20% (Ultrasound Obstet. Gynecol. 2011;38;32-37).

Neither the American College of Obstetricians and Gynecologists nor the Society for Maternal-Fetal Medicine support mandated universal transvaginal ultrasound cervical length screening. Both organizations state, however, that the approach may be considered in women with singleton gestations without prior spontaneous preterm birth.

Interestingly, Thomas Jefferson University in Philadelphia, which uses a universal screening program for singleton gestations without prior preterm birth, has recently published data that complicate the growing trend toward universal cervical length screening.

The Philadelphia clinicians followed a strategy whereby women with a transvaginal cervical length of 2 cm or less were prescribed vaginal progesterone (90 mg vaginal progesterone gel, or 200 mg micronized progesterone gel capsules). Those with a cervical length between approximately 2 cm and 2.5 cm were asked to return for a follow-up cervical length measurement before 24 weeks’ gestation.

What they found in this cohort was surprising: a rate of short cervix that is significantly lower than what previous research has shown.

Among those screened, 0.8% of women had a cervical length of 2 cm or less on an initial transvaginal ultrasonogram. Previously, a prevalence of 1%-2% for an even shorter cervical length (less than 1.5 cm) was fairly consistent in the literature.

As Dr. Kelly M. Orzechowski and her colleagues point out, the low incidence of short cervix “raises questions regarding whether universal transvaginal ultrasonogram cervical length screening in low-risk asymptomatic women is beneficial” (Obstet. Gynecol. 2014;124:520-5).

In our 2011 cost-effectiveness analysis, we found that screening was no longer a cost-saving practice when the incidence of cervical length less than 1.5 cm falls below 0.8%. Screening remained cost effective, however.

Recently, we found that if the Philadelphia protocol is followed and the U.S. population has an incidence of shortened cervix similar to that described by Dr. Orzechowski and her colleagues, universal cervical length screening in low-risk singleton pregnancies is cost effective but not cost saving. Furthermore, we found several additional plausible situations in this unpublished analysis in which universal screening ceased to be cost effective.

Thus, before we move to a strategy of mandated universal screening, we need better population-based estimates of the incidence of short cervix in a truly low-risk population.

We also must consider the future costs of progesterone. It is possible that costs may increase significantly if vaginal progesterone wins approval from the Food and Drug Administration for this indication.

Finally, if universal cervical length screening is to become the standard of care, we need policies in place to prevent misuse of the screening technology that would inevitably drive up costs without improving outcomes. For example, we must ensure that one cervical length measurement does not transition into serial cervical length measurements over the course of pregnancy, since measurement after 24 weeks has limited clinical utility. Similarly, progesterone use for a cervical length less than or equal to 2.0 cm cannot progress to progesterone for anyone approaching 2.0 cm (i.e. 2.5 cm or even 3 cm) as there is no evidence to suggest a benefit for women with longer cervixes.

Over time, it would be beneficial to have additional data on how best to manage patients who have a cervical length of 2 cm-2.5 cm before 24 weeks’ gestation. Many of us ask these women to return for a follow-up measurement and some may prescribe progesterone. However, we lack evidence for either approach; while a cervical length measurement less than 2.5 cm is clearly associated with an increased risk of preterm birth, the benefit of treatment has been demonstrated only with a cervical length of 2 cm or less.

 

Today and the future

For women with a history of preterm birth, cervical length screening is now routine. For low-risk pregnant women – those without a history of previous spontaneous preterm delivery – various approaches are currently taken. Most physicians recommend assessing the cervical length transabdominally at the time of the 18-20-week ultrasound, and proceeding to transvaginal ultrasonography if the cervical length is less than 3 cm or 3.5 cm.

To reliably image the cervix with transabdominal ultrasound, it should be performed with a full bladder and with the understanding that the cervix appears longer (6 mm longer, on average) when the bladder is full (Aust. N. Z. J. Obstet. Gynaecol. 2014;54:250-55).

Transvaginal ultrasound has been widely recognized as a sensitive and reproducible method for detecting shortened cervical length. Overall, this tool has several advantages over the transabdominal approach. However, the lack of universal access to transvaginal ultrasound and to consistently reliable cervical length measurements have been valid concerns of those who oppose universal transvaginal ultrasound cervical length screening.

Such concerns likely will lessen over time as transvaginal ultrasound continues to become more pervasive. Several years ago, the Perinatal Quality Foundation set standards for measuring the cervix and launched the Cervical Length Education and Review (CLEAR) program. When sonographers and physicians obtain training and credentialing, there appears to be only a 5%-10% intraobserver variability in cervical length measurement. (The PQF’s initial focus in 2005 was the Nuchal Translucency Quality Review program.)

Increasingly, I believe, transvaginal ultrasound cervical length measurement will be utilized to identify women at high risk for early preterm birth so that low-risk women can receive progesterone and high-risk women (those with a history of preterm birth) can be considered as candidates for cerclage placement. In the process, the quality of clinical care as well as the quality of our research data will improve. Whether and when such screening will become universal, however, is still uncertain.

Dr. Werner reported that she has no financial disclosures relevant to this Master Class.

Rates of preterm birth in the United States have been falling since 2006, but the rates of early preterm birth in singletons (those under 34 weeks’ gestation), specifically, have not trended downward as dramatically as have late preterm birth in singletons (34-36 weeks). According to 2015 data from the National Vital Statistics Reports, the rate of early preterm births is still 3.4% in all pregnancies and 2.7% among singletons.

While the number of neonates born before 37 weeks of gestation remains high – approximately 11% in 2013 – and signifies a continuing public health problem, the rate of early preterm birth is particularly concerning because early preterm birth is more significantly associated with neonatal mortality, long-term morbidity and extended neonatal intensive care unit stays, all leading to increased health care expenditures.

Finding predictors for preterm birth that are stronger than traditional clinical factors has long been a goal of ob.gyns. because the vast majority of all spontaneous preterm births occur to women without known risk factors (i.e., multiple gestations or prior preterm birth).

Cervical length in the midtrimester is now a well-verified predictor of preterm birth, for both low- and high-risk women. Furthermore, vaginal progesterone has been shown to be a safe and beneficial intervention for women with no known risk factors who are diagnosed with a shortened cervical length (< 2 cm), and cervical cerclage has been suggested to reduce the risk of preterm birth for women with a history of prior preterm birth who also have a shortened cervical length.

Some are now advocating universal cervical length screening for women with singleton gestations, but before universal screening is mandated, the downstream effect of such a change in practice must be considered.

Backdrop to screening

Cervical length measurement was first investigated more than 25 years ago as a possible predictor of preterm birth. In 1996, a prospective multicenter study of almost 3,000 women with singleton pregnancies showed that the risk of preterm delivery is inversely and directly related to the length of the cervix, as measured with vaginal ultrasonography (N. Engl. J. Med. 1996;334:567-72).

In fact, at 24 weeks’ gestation, every 1 mm of additional cervical length equates to a significant decrease in preterm birth risk (odds ratio, 0.91). Several other studies, in addition to the landmark 1996 study, have similarly demonstrated this inverse relationship between preterm birth risk and cervical length between 18 and 24 weeks’ gestation.

However, the use of cervical measurement did not achieve widespread use until more than a decade later, when researchers began to identify interventions that could prolong pregnancy if a short cervix was diagnosed in the second trimester.

For example, Dr. E.B. Fonseca’s study of almost 25,000 asymptomatic pregnant women, demonstrated that daily vaginal progesterone reduced the risk of spontaneous delivery before 34 weeks by approximately 44% in women identified with a cervical length of 1.5 cm or less (N. Engl. J. Med. 2007;357:462-9). The vast majority of the women in this study had singleton pregnancies.

Shortly thereafter, Dr. S.S. Hassan and her colleagues completed a similar trial in women with singleton gestations and transvaginal cervical lengths between 1.0 and 2.0 cm at 20-23 weeks’ gestation. In this trial, nightly progesterone gel (with 90 mg progesterone per application) was associated with a 45% reduction in preterm birth before 33 weeks and a 38% reduction in preterm birth before 35 weeks (Ultrasound. Obstet. Gynecol. 2011;38:18-31).

A meta-analysis led by Dr. Roberto Romero, which included the Fonseca and Hassan trials, looked specifically at 775 women with a midtrimester cervical length of 2.5 cm or less. Women with a singleton gestation who had no history of preterm birth had a 40% reduction in the rate of early preterm birth when they were treated with vaginal progesterone (Am. J. Obstet. Gynecol. 2012;206:124-e1-19).

The benefits of identifying a short cervix likely extend to women with a history of prior preterm birth. A patient-level meta-analysis published in 2011 demonstrated that cervical cerclage placement was associated with a significant reduction in preterm birth before 35 weeks’ gestation in women with singleton gestations, previous spontaneous preterm birth, and cervical length less than 2.5 cm before 24 weeks’ gestation (Obstet. Gynecol. 2011;117:663-71).

The possible benefits of diagnosing and intervening for a shortened cervix have tipped many experts and clinicians toward the practice of universal cervical length screening of all singleton pregnancies. Research has shown that we can accurately obtain a cervical-length measurement before 24 weeks, and that we have effective and safe interventions for cases of short cervix: cerclage in women with a history of preterm birth who are already receiving progesterone, and vaginal progesterone in women without such a history.

 

Screening certainties and doubts

In 2011, my colleagues and I compared the cost effectiveness of two approaches to preterm birth prevention in low-risk pregnancies: no screening versus a single transvaginal ultrasound cervical-length measurement in all asymptomatic, low-risk singleton pregnant individuals between 18 and 24 weeks’ gestation.

In our model, women identified as having a cervical length less than 1.5 cm would be offered vaginal progesterone. Based on published data, we assumed there would be a 92% adherence rate, and a 45% reduction in deliveries before 34 weeks with progesterone treatment.

We found that in low-risk pregnancies, universal transvaginal cervical-length ultrasound screening and progesterone intervention would be cost effective and in many cases cost saving. We estimated that screening would prevent 248 early preterm births – as well as 22 neonatal deaths or neonates with long-term neurologic deficits – per 100,000 deliveries.

Our sensitivity analyses showed that screening remained cost saving under a range of clinical scenarios, including varied preterm birth rates and predictive values of a shortened cervix. Screening was not cost saving, but remained cost effective, when the expense of a transvaginal ultrasound scan exceeds $187 or when vaginal progesterone is assumed to reduce the risk of early preterm delivery by less than 20% (Ultrasound Obstet. Gynecol. 2011;38;32-37).

Neither the American College of Obstetricians and Gynecologists nor the Society for Maternal-Fetal Medicine support mandated universal transvaginal ultrasound cervical length screening. Both organizations state, however, that the approach may be considered in women with singleton gestations without prior spontaneous preterm birth.

Interestingly, Thomas Jefferson University in Philadelphia, which uses a universal screening program for singleton gestations without prior preterm birth, has recently published data that complicate the growing trend toward universal cervical length screening.

The Philadelphia clinicians followed a strategy whereby women with a transvaginal cervical length of 2 cm or less were prescribed vaginal progesterone (90 mg vaginal progesterone gel, or 200 mg micronized progesterone gel capsules). Those with a cervical length between approximately 2 cm and 2.5 cm were asked to return for a follow-up cervical length measurement before 24 weeks’ gestation.

What they found in this cohort was surprising: a rate of short cervix that is significantly lower than what previous research has shown.

Among those screened, 0.8% of women had a cervical length of 2 cm or less on an initial transvaginal ultrasonogram. Previously, a prevalence of 1%-2% for an even shorter cervical length (less than 1.5 cm) was fairly consistent in the literature.

As Dr. Kelly M. Orzechowski and her colleagues point out, the low incidence of short cervix “raises questions regarding whether universal transvaginal ultrasonogram cervical length screening in low-risk asymptomatic women is beneficial” (Obstet. Gynecol. 2014;124:520-5).

In our 2011 cost-effectiveness analysis, we found that screening was no longer a cost-saving practice when the incidence of cervical length less than 1.5 cm falls below 0.8%. Screening remained cost effective, however.

Recently, we found that if the Philadelphia protocol is followed and the U.S. population has an incidence of shortened cervix similar to that described by Dr. Orzechowski and her colleagues, universal cervical length screening in low-risk singleton pregnancies is cost effective but not cost saving. Furthermore, we found several additional plausible situations in this unpublished analysis in which universal screening ceased to be cost effective.

Thus, before we move to a strategy of mandated universal screening, we need better population-based estimates of the incidence of short cervix in a truly low-risk population.

We also must consider the future costs of progesterone. It is possible that costs may increase significantly if vaginal progesterone wins approval from the Food and Drug Administration for this indication.

Finally, if universal cervical length screening is to become the standard of care, we need policies in place to prevent misuse of the screening technology that would inevitably drive up costs without improving outcomes. For example, we must ensure that one cervical length measurement does not transition into serial cervical length measurements over the course of pregnancy, since measurement after 24 weeks has limited clinical utility. Similarly, progesterone use for a cervical length less than or equal to 2.0 cm cannot progress to progesterone for anyone approaching 2.0 cm (i.e. 2.5 cm or even 3 cm) as there is no evidence to suggest a benefit for women with longer cervixes.

Over time, it would be beneficial to have additional data on how best to manage patients who have a cervical length of 2 cm-2.5 cm before 24 weeks’ gestation. Many of us ask these women to return for a follow-up measurement and some may prescribe progesterone. However, we lack evidence for either approach; while a cervical length measurement less than 2.5 cm is clearly associated with an increased risk of preterm birth, the benefit of treatment has been demonstrated only with a cervical length of 2 cm or less.

 

Today and the future

For women with a history of preterm birth, cervical length screening is now routine. For low-risk pregnant women – those without a history of previous spontaneous preterm delivery – various approaches are currently taken. Most physicians recommend assessing the cervical length transabdominally at the time of the 18-20-week ultrasound, and proceeding to transvaginal ultrasonography if the cervical length is less than 3 cm or 3.5 cm.

To reliably image the cervix with transabdominal ultrasound, it should be performed with a full bladder and with the understanding that the cervix appears longer (6 mm longer, on average) when the bladder is full (Aust. N. Z. J. Obstet. Gynaecol. 2014;54:250-55).

Transvaginal ultrasound has been widely recognized as a sensitive and reproducible method for detecting shortened cervical length. Overall, this tool has several advantages over the transabdominal approach. However, the lack of universal access to transvaginal ultrasound and to consistently reliable cervical length measurements have been valid concerns of those who oppose universal transvaginal ultrasound cervical length screening.

Such concerns likely will lessen over time as transvaginal ultrasound continues to become more pervasive. Several years ago, the Perinatal Quality Foundation set standards for measuring the cervix and launched the Cervical Length Education and Review (CLEAR) program. When sonographers and physicians obtain training and credentialing, there appears to be only a 5%-10% intraobserver variability in cervical length measurement. (The PQF’s initial focus in 2005 was the Nuchal Translucency Quality Review program.)

Increasingly, I believe, transvaginal ultrasound cervical length measurement will be utilized to identify women at high risk for early preterm birth so that low-risk women can receive progesterone and high-risk women (those with a history of preterm birth) can be considered as candidates for cerclage placement. In the process, the quality of clinical care as well as the quality of our research data will improve. Whether and when such screening will become universal, however, is still uncertain.

Dr. Werner reported that she has no financial disclosures relevant to this Master Class.

Only recently has paternal postpartum depression (PPD) received much attention. Research has shown that maternal PPD is associated with negative outcomes in the child’s cognitive develop­ment and social and marital problems for the parents. Likewise, depressed fathers are less likely to play outside with their child and more likely to put the child to bed awake.¹

Recent studies reported that 10.4% of men experienced depression within 12 month of delivery.¹ Edmondson et al² estimate the prevalence of paternal PPD to be 8% between birth and 3 months, 26% from 3 to 6 months, and 9% from 6 to 12 months.

Risk factors
Risk factors for paternal PPD have not been studied extensively. Some studies have shown that immaturity, lack of social sup­port, first or unplanned pregnancies, marital relationship problems, and unemployment were the most common risk factors for depression in men postnatally.³ A history of depression and other psychiatric disorders also increases risk.⁴ Psychosocial factors, such as quality of the spousal relationship, parenting distress, and perceived parenting efficacy, contribute to paternal depression.

Similarly, depressed postpartum fathers experience higher levels of parenting dis­tress and a lower sense of parenting effi­cacy.⁵ Interestingly, negative life events were associated with increased risk for depression in mothers, but not fathers.³

Clinical presentation
Paternal PPD symptoms appear within 12 months after the birth of the child and last for at least 2 weeks. Signs and symptoms of depression in men might not resemble those seen in postpartum women. Men tend to show aggression, increased or easy irritabil­ity, and agitation, and might not seek help for emotional issues as readily as women do. Typical symptoms of depression often are present, such as sleep disturbance or changes in sleep patterns, difficulty concen­trating, memory problems, and feelings of worthlessness, hopelessness, inadequacy, and excess guilt with suicidal ideation.⁶

Making the diagnosis
Maternal PPD commonly is evaluated using the Edinburgh Postnatal Depression Scale- Partner (EDPS-P) or Postpartum Depression Screening Scale. However, studies are lack­ing to determine which diagnostic modal­ity is most accurate for diagnosing paternal PPD.

A paternal PPD screening tool could include the EDPS-P administered to moth­ers. Edmonson et al² determined an EDPS-P score of >10 was the optimal cut-off point for screening for paternal depression, with a sensitivity of 89.5% and a specificity of 78.2%, compared with a structured clini­cal interview. Fisher et al⁴ determined that the EDPS-P report was a reliable method for detecting paternal PPD compared with validated depression scales completed by fathers. Madsen et al⁵ determined the Gotland Male Depression Scale, which detects typical male depressive symptoms, also was effective in recognizing paternal PPD at 6 weeks postpartum.⁷

Treatment of paternal PPD
Specific treatment for paternal PPD has not been studied extensively. Psychotherapy targeted at interpersonal family relation­ships and parenting is indicated for mild depression, whereas a combination of psy­chotherapy and pharmacotherapy is recom­mended for moderate or severe depression.

Depending on specific patient factors, pharmacotherapy options include selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibi­tors, tricyclic antidepressants, and atypical antipsychotics.⁸ SSRIs often are used because of their efficacy and relative lack of serious side effects, as demonstrated in numerous trials.² Recovery is more likely with combi­nation therapy than monotherapy.⁹ Fathers with psychosis or suicidal ideation should be referred for inpatient treatment.


Disclosures
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Only recently has paternal postpartum depression (PPD) received much attention. Research has shown that maternal PPD is associated with negative outcomes in the child’s cognitive develop­ment and social and marital problems for the parents. Likewise, depressed fathers are less likely to play outside with their child and more likely to put the child to bed awake.¹

Recent studies reported that 10.4% of men experienced depression within 12 month of delivery.¹ Edmondson et al² estimate the prevalence of paternal PPD to be 8% between birth and 3 months, 26% from 3 to 6 months, and 9% from 6 to 12 months.

Risk factors
Risk factors for paternal PPD have not been studied extensively. Some studies have shown that immaturity, lack of social sup­port, first or unplanned pregnancies, marital relationship problems, and unemployment were the most common risk factors for depression in men postnatally.³ A history of depression and other psychiatric disorders also increases risk.⁴ Psychosocial factors, such as quality of the spousal relationship, parenting distress, and perceived parenting efficacy, contribute to paternal depression.

Similarly, depressed postpartum fathers experience higher levels of parenting dis­tress and a lower sense of parenting effi­cacy.⁵ Interestingly, negative life events were associated with increased risk for depression in mothers, but not fathers.³

Clinical presentation
Paternal PPD symptoms appear within 12 months after the birth of the child and last for at least 2 weeks. Signs and symptoms of depression in men might not resemble those seen in postpartum women. Men tend to show aggression, increased or easy irritabil­ity, and agitation, and might not seek help for emotional issues as readily as women do. Typical symptoms of depression often are present, such as sleep disturbance or changes in sleep patterns, difficulty concen­trating, memory problems, and feelings of worthlessness, hopelessness, inadequacy, and excess guilt with suicidal ideation.⁶

Making the diagnosis
Maternal PPD commonly is evaluated using the Edinburgh Postnatal Depression Scale- Partner (EDPS-P) or Postpartum Depression Screening Scale. However, studies are lack­ing to determine which diagnostic modal­ity is most accurate for diagnosing paternal PPD.

A paternal PPD screening tool could include the EDPS-P administered to moth­ers. Edmonson et al² determined an EDPS-P score of >10 was the optimal cut-off point for screening for paternal depression, with a sensitivity of 89.5% and a specificity of 78.2%, compared with a structured clini­cal interview. Fisher et al⁴ determined that the EDPS-P report was a reliable method for detecting paternal PPD compared with validated depression scales completed by fathers. Madsen et al⁵ determined the Gotland Male Depression Scale, which detects typical male depressive symptoms, also was effective in recognizing paternal PPD at 6 weeks postpartum.⁷

Treatment of paternal PPD
Specific treatment for paternal PPD has not been studied extensively. Psychotherapy targeted at interpersonal family relation­ships and parenting is indicated for mild depression, whereas a combination of psy­chotherapy and pharmacotherapy is recom­mended for moderate or severe depression.

Depending on specific patient factors, pharmacotherapy options include selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibi­tors, tricyclic antidepressants, and atypical antipsychotics.⁸ SSRIs often are used because of their efficacy and relative lack of serious side effects, as demonstrated in numerous trials.² Recovery is more likely with combi­nation therapy than monotherapy.⁹ Fathers with psychosis or suicidal ideation should be referred for inpatient treatment.


Disclosures
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Only recently has paternal postpartum depression (PPD) received much attention. Research has shown that maternal PPD is associated with negative outcomes in the child’s cognitive develop­ment and social and marital problems for the parents. Likewise, depressed fathers are less likely to play outside with their child and more likely to put the child to bed awake.¹

Recent studies reported that 10.4% of men experienced depression within 12 month of delivery.¹ Edmondson et al² estimate the prevalence of paternal PPD to be 8% between birth and 3 months, 26% from 3 to 6 months, and 9% from 6 to 12 months.

Risk factors
Risk factors for paternal PPD have not been studied extensively. Some studies have shown that immaturity, lack of social sup­port, first or unplanned pregnancies, marital relationship problems, and unemployment were the most common risk factors for depression in men postnatally.³ A history of depression and other psychiatric disorders also increases risk.⁴ Psychosocial factors, such as quality of the spousal relationship, parenting distress, and perceived parenting efficacy, contribute to paternal depression.

Similarly, depressed postpartum fathers experience higher levels of parenting dis­tress and a lower sense of parenting effi­cacy.⁵ Interestingly, negative life events were associated with increased risk for depression in mothers, but not fathers.³

Clinical presentation
Paternal PPD symptoms appear within 12 months after the birth of the child and last for at least 2 weeks. Signs and symptoms of depression in men might not resemble those seen in postpartum women. Men tend to show aggression, increased or easy irritabil­ity, and agitation, and might not seek help for emotional issues as readily as women do. Typical symptoms of depression often are present, such as sleep disturbance or changes in sleep patterns, difficulty concen­trating, memory problems, and feelings of worthlessness, hopelessness, inadequacy, and excess guilt with suicidal ideation.⁶

Making the diagnosis
Maternal PPD commonly is evaluated using the Edinburgh Postnatal Depression Scale- Partner (EDPS-P) or Postpartum Depression Screening Scale. However, studies are lack­ing to determine which diagnostic modal­ity is most accurate for diagnosing paternal PPD.

A paternal PPD screening tool could include the EDPS-P administered to moth­ers. Edmonson et al² determined an EDPS-P score of >10 was the optimal cut-off point for screening for paternal depression, with a sensitivity of 89.5% and a specificity of 78.2%, compared with a structured clini­cal interview. Fisher et al⁴ determined that the EDPS-P report was a reliable method for detecting paternal PPD compared with validated depression scales completed by fathers. Madsen et al⁵ determined the Gotland Male Depression Scale, which detects typical male depressive symptoms, also was effective in recognizing paternal PPD at 6 weeks postpartum.⁷

Treatment of paternal PPD
Specific treatment for paternal PPD has not been studied extensively. Psychotherapy targeted at interpersonal family relation­ships and parenting is indicated for mild depression, whereas a combination of psy­chotherapy and pharmacotherapy is recom­mended for moderate or severe depression.

Depending on specific patient factors, pharmacotherapy options include selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibi­tors, tricyclic antidepressants, and atypical antipsychotics.⁸ SSRIs often are used because of their efficacy and relative lack of serious side effects, as demonstrated in numerous trials.² Recovery is more likely with combi­nation therapy than monotherapy.⁹ Fathers with psychosis or suicidal ideation should be referred for inpatient treatment.


Disclosures
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Ah! the dream of opening private practice! Whether you’re a resident making less than minimum wage or a clinic employee seeing ever more patients, the allure is powerful. But, just because you’re whip-smart in matters of the mind, doesn’t mean you know how to run a business. To prevent your dream from succumbing to the siren’s allure, you’ll need to create a blueprint that gets you moving today, as well as prepare sys­tems that will endure over the years.

Establish a business model
Before signing a lease or scheduling patients, think through these fundamental questions, not just from a clinical perspec­tive but a business one as well:
   • What kind of care would you like to provide? If you want to practice psycho­therapy and medication, you’ll have fewer time slots to have to fill, but it may be more challenging to find patients who want and can afford psychotherapy from you as well.
   • Where do you want to practice? Time spent commuting rarely produces income, so how close do you want your office to be to where you live? Being able to walk to work is wonderful, but is where you live the best location for your patients?
For example, downtown areas in big cit­ies are good for providing a critical mass of patients, especially if you only want to manage patients’ medications. But if you want to see children and families, you should consider a location that is friendlier for them—usually more residential areas. Having a coffee shop nearby for waiting parents doesn’t hurt. If you work in a rural area, how easily can patients get to your office?
   • Which hours do you want to work? Many patients will want to see you at “prime time”—before or after their work day or during the weekend. This might, not coincidentally, be when you don’t want to work. Consider whether there is room for compromise: Can you work 1 or 2 early or late days? Can you do 1 weekend day once in a while? If you want to see children, can you regularly be available after school?
   • Will you accept insurance? Pros: The insurance companies will do the marketing for you; your practice will fill quickly; their checks don’t bounce; and, 98% of the time, the claims and payment process works just fine.
Cons: You will make less money per patient, in return for the higher volume of patients that are sent your way; the insur­ance companies won’t want to pay you more than they pay non-psychiatrists for psychotherapy; and the small amount of time that there are administrative problems can consume a disproportionate share of your sanity.

Run the numbers carefully
Next, think about the financial aspect. How much do you need to make, after you’ve paid business expenses and taxes, to be content? You might be tempted to work as many hours as possible, think­ing that every hour off is an hour that you could have billed. Shifting your viewpoint from “hours lost” to “hours free” is a nec­essary approach to reduce burnout.

Once you have figured out your finan­cial goal, do the math: multiply hours/ week × hourly rate × how many weeks/ year you’ll work to determine your annual income. Play around with the numbers to test your priorities, such as optimiz­ing daily hours vs vacation time vs charg­ing more or less.

Build your brand
This is your professional identity—the pic­ture of your practice that your colleagues and future patients will see and that will start to get those hours filled. How will you convey your strengths and personal­ity? The answer: Get out of the office.
   • Take clinicians who will refer patients to you out to lunch (and pick up the tab).
   • Give free talks to psychotherapists or primary care providers. Grand rounds, group practice meetings, or local clinical associations are potential venues. Give the organizer a menu of topic options that con­nect your clinical interests and theirs, and then create a dynamic presentation based on their feedback. Tip: Do not PowerPoint them to tears.
   • Start blogging. If you enjoy writing, use a blog to showcase your talent and expertise. It is free advertising and makes you seem like a trusted authority. However, don’t start a blog unless you can commit to posting regularly.

Proceed thoughtfully; seek advice
As you think through the matrix of issues presented above, each set of answers may lead to a deeper set of questions. Consultation with a colleague or mentor can save you valuable time. Although you don’t have to have all the answers before you open your practice, spending time thinking through these and other issues beforehand will optimize the chance that your dream becomes a reality.

 

Disclosure
Dr. Braslow is the founder of Luminello.com.

Ah! the dream of opening private practice! Whether you’re a resident making less than minimum wage or a clinic employee seeing ever more patients, the allure is powerful. But, just because you’re whip-smart in matters of the mind, doesn’t mean you know how to run a business. To prevent your dream from succumbing to the siren’s allure, you’ll need to create a blueprint that gets you moving today, as well as prepare sys­tems that will endure over the years.

Establish a business model
Before signing a lease or scheduling patients, think through these fundamental questions, not just from a clinical perspec­tive but a business one as well:
   • What kind of care would you like to provide? If you want to practice psycho­therapy and medication, you’ll have fewer time slots to have to fill, but it may be more challenging to find patients who want and can afford psychotherapy from you as well.
   • Where do you want to practice? Time spent commuting rarely produces income, so how close do you want your office to be to where you live? Being able to walk to work is wonderful, but is where you live the best location for your patients?
For example, downtown areas in big cit­ies are good for providing a critical mass of patients, especially if you only want to manage patients’ medications. But if you want to see children and families, you should consider a location that is friendlier for them—usually more residential areas. Having a coffee shop nearby for waiting parents doesn’t hurt. If you work in a rural area, how easily can patients get to your office?
   • Which hours do you want to work? Many patients will want to see you at “prime time”—before or after their work day or during the weekend. This might, not coincidentally, be when you don’t want to work. Consider whether there is room for compromise: Can you work 1 or 2 early or late days? Can you do 1 weekend day once in a while? If you want to see children, can you regularly be available after school?
   • Will you accept insurance? Pros: The insurance companies will do the marketing for you; your practice will fill quickly; their checks don’t bounce; and, 98% of the time, the claims and payment process works just fine.
Cons: You will make less money per patient, in return for the higher volume of patients that are sent your way; the insur­ance companies won’t want to pay you more than they pay non-psychiatrists for psychotherapy; and the small amount of time that there are administrative problems can consume a disproportionate share of your sanity.

Run the numbers carefully
Next, think about the financial aspect. How much do you need to make, after you’ve paid business expenses and taxes, to be content? You might be tempted to work as many hours as possible, think­ing that every hour off is an hour that you could have billed. Shifting your viewpoint from “hours lost” to “hours free” is a nec­essary approach to reduce burnout.

Once you have figured out your finan­cial goal, do the math: multiply hours/ week × hourly rate × how many weeks/ year you’ll work to determine your annual income. Play around with the numbers to test your priorities, such as optimiz­ing daily hours vs vacation time vs charg­ing more or less.

Build your brand
This is your professional identity—the pic­ture of your practice that your colleagues and future patients will see and that will start to get those hours filled. How will you convey your strengths and personal­ity? The answer: Get out of the office.
   • Take clinicians who will refer patients to you out to lunch (and pick up the tab).
   • Give free talks to psychotherapists or primary care providers. Grand rounds, group practice meetings, or local clinical associations are potential venues. Give the organizer a menu of topic options that con­nect your clinical interests and theirs, and then create a dynamic presentation based on their feedback. Tip: Do not PowerPoint them to tears.
   • Start blogging. If you enjoy writing, use a blog to showcase your talent and expertise. It is free advertising and makes you seem like a trusted authority. However, don’t start a blog unless you can commit to posting regularly.

Proceed thoughtfully; seek advice
As you think through the matrix of issues presented above, each set of answers may lead to a deeper set of questions. Consultation with a colleague or mentor can save you valuable time. Although you don’t have to have all the answers before you open your practice, spending time thinking through these and other issues beforehand will optimize the chance that your dream becomes a reality.

 

Disclosure
Dr. Braslow is the founder of Luminello.com.

Ah! the dream of opening private practice! Whether you’re a resident making less than minimum wage or a clinic employee seeing ever more patients, the allure is powerful. But, just because you’re whip-smart in matters of the mind, doesn’t mean you know how to run a business. To prevent your dream from succumbing to the siren’s allure, you’ll need to create a blueprint that gets you moving today, as well as prepare sys­tems that will endure over the years.

Establish a business model
Before signing a lease or scheduling patients, think through these fundamental questions, not just from a clinical perspec­tive but a business one as well:
   • What kind of care would you like to provide? If you want to practice psycho­therapy and medication, you’ll have fewer time slots to have to fill, but it may be more challenging to find patients who want and can afford psychotherapy from you as well.
   • Where do you want to practice? Time spent commuting rarely produces income, so how close do you want your office to be to where you live? Being able to walk to work is wonderful, but is where you live the best location for your patients?
For example, downtown areas in big cit­ies are good for providing a critical mass of patients, especially if you only want to manage patients’ medications. But if you want to see children and families, you should consider a location that is friendlier for them—usually more residential areas. Having a coffee shop nearby for waiting parents doesn’t hurt. If you work in a rural area, how easily can patients get to your office?
   • Which hours do you want to work? Many patients will want to see you at “prime time”—before or after their work day or during the weekend. This might, not coincidentally, be when you don’t want to work. Consider whether there is room for compromise: Can you work 1 or 2 early or late days? Can you do 1 weekend day once in a while? If you want to see children, can you regularly be available after school?
   • Will you accept insurance? Pros: The insurance companies will do the marketing for you; your practice will fill quickly; their checks don’t bounce; and, 98% of the time, the claims and payment process works just fine.
Cons: You will make less money per patient, in return for the higher volume of patients that are sent your way; the insur­ance companies won’t want to pay you more than they pay non-psychiatrists for psychotherapy; and the small amount of time that there are administrative problems can consume a disproportionate share of your sanity.

Run the numbers carefully
Next, think about the financial aspect. How much do you need to make, after you’ve paid business expenses and taxes, to be content? You might be tempted to work as many hours as possible, think­ing that every hour off is an hour that you could have billed. Shifting your viewpoint from “hours lost” to “hours free” is a nec­essary approach to reduce burnout.

Once you have figured out your finan­cial goal, do the math: multiply hours/ week × hourly rate × how many weeks/ year you’ll work to determine your annual income. Play around with the numbers to test your priorities, such as optimiz­ing daily hours vs vacation time vs charg­ing more or less.

Build your brand
This is your professional identity—the pic­ture of your practice that your colleagues and future patients will see and that will start to get those hours filled. How will you convey your strengths and personal­ity? The answer: Get out of the office.
   • Take clinicians who will refer patients to you out to lunch (and pick up the tab).
   • Give free talks to psychotherapists or primary care providers. Grand rounds, group practice meetings, or local clinical associations are potential venues. Give the organizer a menu of topic options that con­nect your clinical interests and theirs, and then create a dynamic presentation based on their feedback. Tip: Do not PowerPoint them to tears.
   • Start blogging. If you enjoy writing, use a blog to showcase your talent and expertise. It is free advertising and makes you seem like a trusted authority. However, don’t start a blog unless you can commit to posting regularly.

Proceed thoughtfully; seek advice
As you think through the matrix of issues presented above, each set of answers may lead to a deeper set of questions. Consultation with a colleague or mentor can save you valuable time. Although you don’t have to have all the answers before you open your practice, spending time thinking through these and other issues beforehand will optimize the chance that your dream becomes a reality.

 

Disclosure
Dr. Braslow is the founder of Luminello.com.

CASE Confused and weak
Mr. W, age 26, is brought to the emergency department (ED) by his parents for intermit­tent confusion, weakness, and increasing lethargy over the past 4 days. He is jaun­diced with mild abdominal pain, nausea, and vomiting.

Mr. W has a history of alcohol use disorder, drinking as much as 1 L of vodka a day. Six months ago, he was hospitalized for alcoholic hepatitis and severe hyponatremia.

In the ED, Mr. W is awake, alert, and ori­ented to person, place, and time. Vital signs are: pulse 89 beats per minute; blood pres­sure, 117/50 mm Hg; respirations, 15 breaths per minute; and temperature, 98.5ºF. Physical examination is notable for scleral icterus, jaun­dice, tender hepatomegaly, and asterixis.

Mr. W is not taking any medications. He reports that his most recent drink was the day before; however, his current alcohol intake is unknown.

Laboratory tests reveal altered hepatic func­tion, including elevated aspartate aminotrans­ferase (251 U/L), alanine aminotransferase (56 U/L), alkaline phosphatase (179 U/L), total bilirubin (15.4 mg/dL), and ammonia (143 U/L), impaired coagulation (international normalized ratio 2.39), and decreased albumin (2.7 g/dL). Other metabolic disturbances include: sodium, 104 mEq/L; chloride, <60 mEq/L; potassium, 2.2 mEq/L; and CO2, 44.5 mEq/L.

What is your differential diagnosis for Mr. W’s altered mental status?
   a) hepatic encephalopathy
   b) Wernicke’s encephalopathy
   c) hyponatremia
   d) drug intoxication
   e) head trauma

The authors’ observations
Hyponatremia is defined as a serum sodium concentration <136 mEq/L. Mr. W is considered to have severe hyponatremia because his serum sodium concentration is <125 mEq/L. Although commonly caused by an inability to suppress antidiuretic hormone, hyponatremia has several pos­sible causes (Figure 1).¹ Symptoms are nonspecific and are more visible when there is a large or rapid decrease in the serum sodium concentration. Most patients with a serum sodium concentration >125 mEq/L are asymptomatic. Mr. W, who had a serum sodium of 104 mEq/L, presented with several symptoms, includ­ing confusion, lethargy, nausea, vomiting, and weakness. Headache, muscle spasms, depressed reflexes, restlessness, and disori­entation also might be observed.²

Because of Mr. W’s impaired hepatic func­tion, elevated ammonia, and asterixis, hepatic encephalopathy could be contributing to his altered mental status. Suspect Wernicke’s encephalopathy in a patient with neurologic symptoms and a history of chronic alcohol abuse. In its classic form, Wernicke’s enceph­alopathy has acute onset, characterized by the triad of ataxia, global confusion, and ocu­lar abnormalities. However, this triad is not consistently or frequently encountered.³

Which tests would you order next?
   a) blood ethanol level
   b) urine drug screen
   c) serum osmolality
   d) CT of the head

 

EVALUATION Sober, yet sick
To rule out intoxication as the cause of Mr. W’s altered mental status, blood ethanol level and urine drug screens are obtained and found to be negative. CT of the head is negative for acute intracranial pathology.

Mr. W is admitted to the medical intensive care unit (MICU) for severe hyponatremia and altered mental status. Serum osmolality is 220 mOsm/kg (normal range 281 to 304 mOsm/kg). To further classify his hypo­tonic hyponatremia, volume status is assessed, and Mr. W is determined to be euvolemic. Thyroid-stimulating hormone and cortisol are within normal limits, eliminating hypothy­roidism and adrenal insufficiency as causes of his euvolemic hypotonic hyponatremia. Mr. W is treated for hyponatremia likely sec­ondary to syndrome of inappropriate antidi­uretic hormone (SIADH). SIADH is a diagnosis of exclusion that first requires ruling out hypo­thyroidism and glucocorticoid insufficiency (Figure 1).¹

The authors’ observations
Because hypokalemia is an independent pre­dictive factor for development of hyponatre­mia, it is necessary to evaluate the potassium level in all hyponatremic patients. Mr. W’s potassium level was 2.2 mEq/L on admis­sion. Serum sodium concentration is related to total exchangeable sodium, total body water, and total exchangeable potassium. Potassium depletion causes a shift of sodium into cells with a comparable exit of potas­sium from cells into extracellular fluid. The reverse process occurs during potassium repletion, leading to an increase in serum sodium concentration and making hypoka­lemia a risk factor for developing osmotic demyelination syndrome (ODS).⁴

Treating hyponatremia
Hyponatremia treatment depends on its severity, presence or absence of symptoms, and whether the hyponatremia is acute (<24 hours) or chronic (>48 hours).⁵

Because of Mr. W’s extremely low serum sodium concentration, predisposition to hyponatremia secondary to alcoholism, and history of severe hyponatremia, it is likely he is chronically hyponatremic.

In patients with chronic hyponatremia, neurological sequelae are associated with the need for a more rapid rate of correction of serum sodium. For most patients with chronic hyponatremia, a correction rate of ≤10 to 12 mEq/L during the first 24 hours and <18 mEq/L over 48 hours is recom­mended to avoid ODS.⁶

 

Evidence suggests, however, that this 1-day limit might be too high for some patients. Alcoholism, hypokalemia, mal­nutrition, and liver disease are present in a high percentage of patients who develop

ODS after correcting hyponatremia (Table 1).⁶ Therefore, for patients such as Mr. W who are at high risk of ODS, experts recommend a goal of 4 to 6 mEq/L/d with a correction rate of ≤8 mEq/L in any 24-hour period (Table 2).⁶

 

TREATMENT Sodium normalizes
Mr. W receives 1 L of normal saline in the ED before admission to the MICU. Once in the MICU, despite likely chronic hyponatremia, he receives hypertonic (3%) saline, followed by normal saline. Initially, he responds when the serum sodium concentration improves. Because of his likely SIADH, Mr. W is fluid-restricted for 4 days. Serum sodium returns to normal over 7 hospital days (Figure 2). To address the pro­found hypokalemia, Mr. S receives 30 mEq of potassium chloride in the ED, and potas­sium is repeated daily throughout his stay in the MICU.

Mr. W remains lethargic, with intermittent periods of confusion throughout the hospital stay. His altered mental status is attributed to hepatic encephalopathy secondary to alco­holic hepatitis. The Maddrey discriminant function is a calculation that stratifies patients with alcoholic hepatitis for risk of mortal­ity and the use of steroids. Because Mr. W shows a Maddrey discriminant function ≥32, he receives methylprednisolone, followed by pentoxifylline, and liver function tests trend down. He also receives lactulose throughout hospitalization.

By discharge on hospital day 9, Mr. W’s serum sodium is 138 mEq/L; serum potas­sium, 4.1 mEq/L. Total bilirubin and prothrom­bin remain elevated. Mr. W is discharged on lactulose, thiamine, folic acid, and a 1-month course of pentoxifylline, 400 mg, 3 times a day.

READMISSION Unsteady gait, nausea
Three days after discharge, Mr. W returns to the ED after experiencing a 20-second epi­sode of total body rigidity. He has an unsteady gait and worsening nausea and vomiting.

When Mr. W arrives in the ED, he confirms he is taking his discharge medications as pre­scribed. His parents report that he has con­sumed alcohol and Cannabis since discharge and has been taking his sibling’s prescription medications, including quetiapine.

In the ED, Mr. W is awake, alert, and ori­ented to person, place, and time. Vital signs are: pulse, 118 beats per minute; blood pres­sure, 128/73 mm Hg; respirations, 16 breaths per minute; and temperature, 98.5ºF. Physical examination, again, is notable for scleral icterus, jaundice, and asterixis. No focal neu­rologic deficits are noted.

Consistent with Mr. W’s previous admis­sion, laboratory values reveal altered hepatic function and impaired coagulation. The serum sodium level remains within normal limits at 136 mEq/L. However, again, meta­bolic disturbances include decreased chloride (97 mEq/L), potassium (2.9 mEq/L), and CO2 (18.2 mEq/L). CT on readmission is unchanged from the earlier hospitalization.

What is your differential diagnosis for Mr. W’s total body rigidity?
   a) seizure
   b) ODS
   c) drug intoxication
   d) neuroleptic malignant syndrome

EVALUATION Shaking and weakness
Once admitted to the hospital, Mr. W reports an episode of right upper-extremity “shak­ing,” followed by weakness. He remembers the entire event and denies tongue biting or incontinence. He is evaluated for pos­sible seizure, given his multiple risk factors, including drug and alcohol use, ingestion of quetiapine, and history of hyponatremia. Routine EEG is negative but prolactin level is elevated.

Mr. W’s mental status continues to wax and wane, prompting a neurology consult and MRI for further evaluation. MRI of the brain without contrast reveals restricted diffusion in the pons centrally, with extension bilaterally to the midbrain and thalami—findings con­sistent with central pontine myelinolysis. A neurology consultation reveals quadriparesis, paraparesis, dysarthria, and diplopia on exam­ination, all symptoms associated with central pontine myelinolysis.

The authors’ observations
ODS, including central and extrapontine myelinolysis, is a demyelinating condi­tion that occurs because of severe osmotic stress, most commonly secondary to the overly rapid correction of hyponatremia in patients with conditions leading to nutritional or electrolyte stress.⁷ Mr. W is considered at high risk of developing ODS because he fulfills the 5 criteria listed in Table 1.

Several psychiatric illnesses and neu­ropsychiatric medications could lead to hyponatremia. Many studies^8-10 have docu­mented hyponatremia and resulting ODS in patients with alcoholism, schizophrenia, anorexia, primary psychogenic polydipsia, and MDMA (3,4-methylenedioxymetham­phetamine) abuse. Hyponatremia is a side effect of several neuropsychiatric medica­tions, including serotonin reuptake inhibi­tors, lithium, tricyclic antidepressants, opioids, carbamazepine, oxcarbazepine, and antipsychotic polypharmacy. Other commonly used medications associated with hyponatremia include salt-losing diuretics, nonsteroidal anti-inflammatory drugs, and acetaminophen.⁷

Disease severity varies from asymptom­atic to coma or death. Symptoms, although some could reverse completely, typically are a combination of neuropsychiatric (ie, emotional lability, disinhibition, and other bizarre behaviors) and neurologic. Neurologic symptoms include confusion, impaired cognition, dysarthria, dyspha­gia, gait instability, weakness or paralysis, and generalized seizures. Severely affected patients could experience “locked-in syn­drome,” in which they are awake but unable to move or communicate. Also consistent with Mr. W’s case, ODS often presents ini­tially with delirium, seizures, or encepha­lopathy, followed by a lucid interval before symptoms develop.⁷

 

Diagnosis is based on the appearance of demyelinating brain lesions on CT or MRI. MRI is more sensitive than CT; however, even an MRI scan can appear normal for as long as 4 weeks after symptoms appear.⁷ Therefore, an initial negative radiologic study in a high-risk patient who develops neurologic symptoms does not exclude ODS. Earlier detection is possible with dif­fusion-weighted MRI, which is most sensi­tive and can detect lesions within 24 hours of developing symptoms.¹¹ The severity of the lesion does not correlate with severity of symptoms.

Studies reveal a considerable range in prognosis of patients with clinically symp­tomatic ODS. A study of 44 patients with central pontine myelinolysis, of which 42 had chronic alcoholism, reported that 34% had no significant functional deficits at follow-up, 34% had minor neurologic defi­cits, and 31% became dependent on per­sonal help. Outcome did not depend on the extent or severity of neurologic symptoms or the severity of concomitant systemic complications.¹²

Because of its poor prognosis, prevention of ODS is important. Because ODS com­monly is caused by overly rapid correction of hyponatremia, it is necessary to adhere to guidelines for treating chronic hypona­tremia (Table 2). If overcorrection occurs, therapeutic re-lowering of serum sodium can be considered, but has not been validated in controlled trials. Based mainly on case reports that suggest benefit from early re-lowering serum sodium in patients with ODS symptoms, experts recommend the following:  
   • administer desmopressin, 2 to 4 μg, every 8 hours parenterally  
   • replace water orally or as 5% dextrose in water intravenously (3 mL/kg/hr)  
   • check serum sodium hourly until serum is reduced to goal.⁶

Bottom Line

Hyponatremia is the most common electrolyte disorder encountered in practice. Osmotic demyelination syndrome often is preventable, with considerable morbidity and mortality. Psychiatrists should be aware of this condition because it could be an adverse effect of many psychiatric medications and there are some psychiatric illnesses in which hyponatremia is a potential risk. In hyponatremic patients with persistent nonspecific neurologic or neuropsychiatric symptoms and negative CT imaging, additional imaging, such as MRI, is warranted.

Related Resources

• Braun MM, Barstow CH, Pyzocha NJ. Diagnosis and management of sodium disorders: hyponatremia and hypernatremia. Am Fam Physician. 2015;91(5):299-307.
• Vaidya C, Ho W, Freda BJ. Management of hyponatremia: providing treatment and avoiding harm. Cleve Clin J Med. 2010;77(10):715-726.

Drug Brand Names
Carbamazepine • Tegretol
Oxcarbazepine • Trileptal
Desmopressin • Stimate, DDAVP
Lithium • Eskalith, Lithobid
Pentoxifylline • Trental, Pentoxil
Methylprednisolone • Medrol
Quetiapine • Seroquel

Disclosure
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

CASE Confused and weak
Mr. W, age 26, is brought to the emergency department (ED) by his parents for intermit­tent confusion, weakness, and increasing lethargy over the past 4 days. He is jaun­diced with mild abdominal pain, nausea, and vomiting.

Mr. W has a history of alcohol use disorder, drinking as much as 1 L of vodka a day. Six months ago, he was hospitalized for alcoholic hepatitis and severe hyponatremia.

In the ED, Mr. W is awake, alert, and ori­ented to person, place, and time. Vital signs are: pulse 89 beats per minute; blood pres­sure, 117/50 mm Hg; respirations, 15 breaths per minute; and temperature, 98.5ºF. Physical examination is notable for scleral icterus, jaun­dice, tender hepatomegaly, and asterixis.

Mr. W is not taking any medications. He reports that his most recent drink was the day before; however, his current alcohol intake is unknown.

Laboratory tests reveal altered hepatic func­tion, including elevated aspartate aminotrans­ferase (251 U/L), alanine aminotransferase (56 U/L), alkaline phosphatase (179 U/L), total bilirubin (15.4 mg/dL), and ammonia (143 U/L), impaired coagulation (international normalized ratio 2.39), and decreased albumin (2.7 g/dL). Other metabolic disturbances include: sodium, 104 mEq/L; chloride, <60 mEq/L; potassium, 2.2 mEq/L; and CO2, 44.5 mEq/L.

What is your differential diagnosis for Mr. W’s altered mental status?
   a) hepatic encephalopathy
   b) Wernicke’s encephalopathy
   c) hyponatremia
   d) drug intoxication
   e) head trauma

The authors’ observations
Hyponatremia is defined as a serum sodium concentration <136 mEq/L. Mr. W is considered to have severe hyponatremia because his serum sodium concentration is <125 mEq/L. Although commonly caused by an inability to suppress antidiuretic hormone, hyponatremia has several pos­sible causes (Figure 1).¹ Symptoms are nonspecific and are more visible when there is a large or rapid decrease in the serum sodium concentration. Most patients with a serum sodium concentration >125 mEq/L are asymptomatic. Mr. W, who had a serum sodium of 104 mEq/L, presented with several symptoms, includ­ing confusion, lethargy, nausea, vomiting, and weakness. Headache, muscle spasms, depressed reflexes, restlessness, and disori­entation also might be observed.²

Because of Mr. W’s impaired hepatic func­tion, elevated ammonia, and asterixis, hepatic encephalopathy could be contributing to his altered mental status. Suspect Wernicke’s encephalopathy in a patient with neurologic symptoms and a history of chronic alcohol abuse. In its classic form, Wernicke’s enceph­alopathy has acute onset, characterized by the triad of ataxia, global confusion, and ocu­lar abnormalities. However, this triad is not consistently or frequently encountered.³

Which tests would you order next?
   a) blood ethanol level
   b) urine drug screen
   c) serum osmolality
   d) CT of the head

 

EVALUATION Sober, yet sick
To rule out intoxication as the cause of Mr. W’s altered mental status, blood ethanol level and urine drug screens are obtained and found to be negative. CT of the head is negative for acute intracranial pathology.

Mr. W is admitted to the medical intensive care unit (MICU) for severe hyponatremia and altered mental status. Serum osmolality is 220 mOsm/kg (normal range 281 to 304 mOsm/kg). To further classify his hypo­tonic hyponatremia, volume status is assessed, and Mr. W is determined to be euvolemic. Thyroid-stimulating hormone and cortisol are within normal limits, eliminating hypothy­roidism and adrenal insufficiency as causes of his euvolemic hypotonic hyponatremia. Mr. W is treated for hyponatremia likely sec­ondary to syndrome of inappropriate antidi­uretic hormone (SIADH). SIADH is a diagnosis of exclusion that first requires ruling out hypo­thyroidism and glucocorticoid insufficiency (Figure 1).¹

The authors’ observations
Because hypokalemia is an independent pre­dictive factor for development of hyponatre­mia, it is necessary to evaluate the potassium level in all hyponatremic patients. Mr. W’s potassium level was 2.2 mEq/L on admis­sion. Serum sodium concentration is related to total exchangeable sodium, total body water, and total exchangeable potassium. Potassium depletion causes a shift of sodium into cells with a comparable exit of potas­sium from cells into extracellular fluid. The reverse process occurs during potassium repletion, leading to an increase in serum sodium concentration and making hypoka­lemia a risk factor for developing osmotic demyelination syndrome (ODS).⁴

Treating hyponatremia
Hyponatremia treatment depends on its severity, presence or absence of symptoms, and whether the hyponatremia is acute (<24 hours) or chronic (>48 hours).⁵

Because of Mr. W’s extremely low serum sodium concentration, predisposition to hyponatremia secondary to alcoholism, and history of severe hyponatremia, it is likely he is chronically hyponatremic.

In patients with chronic hyponatremia, neurological sequelae are associated with the need for a more rapid rate of correction of serum sodium. For most patients with chronic hyponatremia, a correction rate of ≤10 to 12 mEq/L during the first 24 hours and <18 mEq/L over 48 hours is recom­mended to avoid ODS.⁶

 

Evidence suggests, however, that this 1-day limit might be too high for some patients. Alcoholism, hypokalemia, mal­nutrition, and liver disease are present in a high percentage of patients who develop

ODS after correcting hyponatremia (Table 1).⁶ Therefore, for patients such as Mr. W who are at high risk of ODS, experts recommend a goal of 4 to 6 mEq/L/d with a correction rate of ≤8 mEq/L in any 24-hour period (Table 2).⁶

 

TREATMENT Sodium normalizes
Mr. W receives 1 L of normal saline in the ED before admission to the MICU. Once in the MICU, despite likely chronic hyponatremia, he receives hypertonic (3%) saline, followed by normal saline. Initially, he responds when the serum sodium concentration improves. Because of his likely SIADH, Mr. W is fluid-restricted for 4 days. Serum sodium returns to normal over 7 hospital days (Figure 2). To address the pro­found hypokalemia, Mr. S receives 30 mEq of potassium chloride in the ED, and potas­sium is repeated daily throughout his stay in the MICU.

Mr. W remains lethargic, with intermittent periods of confusion throughout the hospital stay. His altered mental status is attributed to hepatic encephalopathy secondary to alco­holic hepatitis. The Maddrey discriminant function is a calculation that stratifies patients with alcoholic hepatitis for risk of mortal­ity and the use of steroids. Because Mr. W shows a Maddrey discriminant function ≥32, he receives methylprednisolone, followed by pentoxifylline, and liver function tests trend down. He also receives lactulose throughout hospitalization.

By discharge on hospital day 9, Mr. W’s serum sodium is 138 mEq/L; serum potas­sium, 4.1 mEq/L. Total bilirubin and prothrom­bin remain elevated. Mr. W is discharged on lactulose, thiamine, folic acid, and a 1-month course of pentoxifylline, 400 mg, 3 times a day.

READMISSION Unsteady gait, nausea
Three days after discharge, Mr. W returns to the ED after experiencing a 20-second epi­sode of total body rigidity. He has an unsteady gait and worsening nausea and vomiting.

When Mr. W arrives in the ED, he confirms he is taking his discharge medications as pre­scribed. His parents report that he has con­sumed alcohol and Cannabis since discharge and has been taking his sibling’s prescription medications, including quetiapine.

In the ED, Mr. W is awake, alert, and ori­ented to person, place, and time. Vital signs are: pulse, 118 beats per minute; blood pres­sure, 128/73 mm Hg; respirations, 16 breaths per minute; and temperature, 98.5ºF. Physical examination, again, is notable for scleral icterus, jaundice, and asterixis. No focal neu­rologic deficits are noted.

Consistent with Mr. W’s previous admis­sion, laboratory values reveal altered hepatic function and impaired coagulation. The serum sodium level remains within normal limits at 136 mEq/L. However, again, meta­bolic disturbances include decreased chloride (97 mEq/L), potassium (2.9 mEq/L), and CO2 (18.2 mEq/L). CT on readmission is unchanged from the earlier hospitalization.

What is your differential diagnosis for Mr. W’s total body rigidity?
   a) seizure
   b) ODS
   c) drug intoxication
   d) neuroleptic malignant syndrome

EVALUATION Shaking and weakness
Once admitted to the hospital, Mr. W reports an episode of right upper-extremity “shak­ing,” followed by weakness. He remembers the entire event and denies tongue biting or incontinence. He is evaluated for pos­sible seizure, given his multiple risk factors, including drug and alcohol use, ingestion of quetiapine, and history of hyponatremia. Routine EEG is negative but prolactin level is elevated.

Mr. W’s mental status continues to wax and wane, prompting a neurology consult and MRI for further evaluation. MRI of the brain without contrast reveals restricted diffusion in the pons centrally, with extension bilaterally to the midbrain and thalami—findings con­sistent with central pontine myelinolysis. A neurology consultation reveals quadriparesis, paraparesis, dysarthria, and diplopia on exam­ination, all symptoms associated with central pontine myelinolysis.

The authors’ observations
ODS, including central and extrapontine myelinolysis, is a demyelinating condi­tion that occurs because of severe osmotic stress, most commonly secondary to the overly rapid correction of hyponatremia in patients with conditions leading to nutritional or electrolyte stress.⁷ Mr. W is considered at high risk of developing ODS because he fulfills the 5 criteria listed in Table 1.

Several psychiatric illnesses and neu­ropsychiatric medications could lead to hyponatremia. Many studies^8-10 have docu­mented hyponatremia and resulting ODS in patients with alcoholism, schizophrenia, anorexia, primary psychogenic polydipsia, and MDMA (3,4-methylenedioxymetham­phetamine) abuse. Hyponatremia is a side effect of several neuropsychiatric medica­tions, including serotonin reuptake inhibi­tors, lithium, tricyclic antidepressants, opioids, carbamazepine, oxcarbazepine, and antipsychotic polypharmacy. Other commonly used medications associated with hyponatremia include salt-losing diuretics, nonsteroidal anti-inflammatory drugs, and acetaminophen.⁷

Disease severity varies from asymptom­atic to coma or death. Symptoms, although some could reverse completely, typically are a combination of neuropsychiatric (ie, emotional lability, disinhibition, and other bizarre behaviors) and neurologic. Neurologic symptoms include confusion, impaired cognition, dysarthria, dyspha­gia, gait instability, weakness or paralysis, and generalized seizures. Severely affected patients could experience “locked-in syn­drome,” in which they are awake but unable to move or communicate. Also consistent with Mr. W’s case, ODS often presents ini­tially with delirium, seizures, or encepha­lopathy, followed by a lucid interval before symptoms develop.⁷

 

Diagnosis is based on the appearance of demyelinating brain lesions on CT or MRI. MRI is more sensitive than CT; however, even an MRI scan can appear normal for as long as 4 weeks after symptoms appear.⁷ Therefore, an initial negative radiologic study in a high-risk patient who develops neurologic symptoms does not exclude ODS. Earlier detection is possible with dif­fusion-weighted MRI, which is most sensi­tive and can detect lesions within 24 hours of developing symptoms.¹¹ The severity of the lesion does not correlate with severity of symptoms.

Studies reveal a considerable range in prognosis of patients with clinically symp­tomatic ODS. A study of 44 patients with central pontine myelinolysis, of which 42 had chronic alcoholism, reported that 34% had no significant functional deficits at follow-up, 34% had minor neurologic defi­cits, and 31% became dependent on per­sonal help. Outcome did not depend on the extent or severity of neurologic symptoms or the severity of concomitant systemic complications.¹²

Because of its poor prognosis, prevention of ODS is important. Because ODS com­monly is caused by overly rapid correction of hyponatremia, it is necessary to adhere to guidelines for treating chronic hypona­tremia (Table 2). If overcorrection occurs, therapeutic re-lowering of serum sodium can be considered, but has not been validated in controlled trials. Based mainly on case reports that suggest benefit from early re-lowering serum sodium in patients with ODS symptoms, experts recommend the following:  
   • administer desmopressin, 2 to 4 μg, every 8 hours parenterally  
   • replace water orally or as 5% dextrose in water intravenously (3 mL/kg/hr)  
   • check serum sodium hourly until serum is reduced to goal.⁶

Bottom Line

Hyponatremia is the most common electrolyte disorder encountered in practice. Osmotic demyelination syndrome often is preventable, with considerable morbidity and mortality. Psychiatrists should be aware of this condition because it could be an adverse effect of many psychiatric medications and there are some psychiatric illnesses in which hyponatremia is a potential risk. In hyponatremic patients with persistent nonspecific neurologic or neuropsychiatric symptoms and negative CT imaging, additional imaging, such as MRI, is warranted.

Related Resources

• Braun MM, Barstow CH, Pyzocha NJ. Diagnosis and management of sodium disorders: hyponatremia and hypernatremia. Am Fam Physician. 2015;91(5):299-307.
• Vaidya C, Ho W, Freda BJ. Management of hyponatremia: providing treatment and avoiding harm. Cleve Clin J Med. 2010;77(10):715-726.

Drug Brand Names
Carbamazepine • Tegretol
Oxcarbazepine • Trileptal
Desmopressin • Stimate, DDAVP
Lithium • Eskalith, Lithobid
Pentoxifylline • Trental, Pentoxil
Methylprednisolone • Medrol
Quetiapine • Seroquel

Disclosure
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

CASE Confused and weak
Mr. W, age 26, is brought to the emergency department (ED) by his parents for intermit­tent confusion, weakness, and increasing lethargy over the past 4 days. He is jaun­diced with mild abdominal pain, nausea, and vomiting.

Mr. W has a history of alcohol use disorder, drinking as much as 1 L of vodka a day. Six months ago, he was hospitalized for alcoholic hepatitis and severe hyponatremia.

In the ED, Mr. W is awake, alert, and ori­ented to person, place, and time. Vital signs are: pulse 89 beats per minute; blood pres­sure, 117/50 mm Hg; respirations, 15 breaths per minute; and temperature, 98.5ºF. Physical examination is notable for scleral icterus, jaun­dice, tender hepatomegaly, and asterixis.

Mr. W is not taking any medications. He reports that his most recent drink was the day before; however, his current alcohol intake is unknown.

Laboratory tests reveal altered hepatic func­tion, including elevated aspartate aminotrans­ferase (251 U/L), alanine aminotransferase (56 U/L), alkaline phosphatase (179 U/L), total bilirubin (15.4 mg/dL), and ammonia (143 U/L), impaired coagulation (international normalized ratio 2.39), and decreased albumin (2.7 g/dL). Other metabolic disturbances include: sodium, 104 mEq/L; chloride, <60 mEq/L; potassium, 2.2 mEq/L; and CO2, 44.5 mEq/L.

What is your differential diagnosis for Mr. W’s altered mental status?
   a) hepatic encephalopathy
   b) Wernicke’s encephalopathy
   c) hyponatremia
   d) drug intoxication
   e) head trauma

The authors’ observations
Hyponatremia is defined as a serum sodium concentration <136 mEq/L. Mr. W is considered to have severe hyponatremia because his serum sodium concentration is <125 mEq/L. Although commonly caused by an inability to suppress antidiuretic hormone, hyponatremia has several pos­sible causes (Figure 1).¹ Symptoms are nonspecific and are more visible when there is a large or rapid decrease in the serum sodium concentration. Most patients with a serum sodium concentration >125 mEq/L are asymptomatic. Mr. W, who had a serum sodium of 104 mEq/L, presented with several symptoms, includ­ing confusion, lethargy, nausea, vomiting, and weakness. Headache, muscle spasms, depressed reflexes, restlessness, and disori­entation also might be observed.²

Because of Mr. W’s impaired hepatic func­tion, elevated ammonia, and asterixis, hepatic encephalopathy could be contributing to his altered mental status. Suspect Wernicke’s encephalopathy in a patient with neurologic symptoms and a history of chronic alcohol abuse. In its classic form, Wernicke’s enceph­alopathy has acute onset, characterized by the triad of ataxia, global confusion, and ocu­lar abnormalities. However, this triad is not consistently or frequently encountered.³

Which tests would you order next?
   a) blood ethanol level
   b) urine drug screen
   c) serum osmolality
   d) CT of the head

 

EVALUATION Sober, yet sick
To rule out intoxication as the cause of Mr. W’s altered mental status, blood ethanol level and urine drug screens are obtained and found to be negative. CT of the head is negative for acute intracranial pathology.

Mr. W is admitted to the medical intensive care unit (MICU) for severe hyponatremia and altered mental status. Serum osmolality is 220 mOsm/kg (normal range 281 to 304 mOsm/kg). To further classify his hypo­tonic hyponatremia, volume status is assessed, and Mr. W is determined to be euvolemic. Thyroid-stimulating hormone and cortisol are within normal limits, eliminating hypothy­roidism and adrenal insufficiency as causes of his euvolemic hypotonic hyponatremia. Mr. W is treated for hyponatremia likely sec­ondary to syndrome of inappropriate antidi­uretic hormone (SIADH). SIADH is a diagnosis of exclusion that first requires ruling out hypo­thyroidism and glucocorticoid insufficiency (Figure 1).¹

The authors’ observations
Because hypokalemia is an independent pre­dictive factor for development of hyponatre­mia, it is necessary to evaluate the potassium level in all hyponatremic patients. Mr. W’s potassium level was 2.2 mEq/L on admis­sion. Serum sodium concentration is related to total exchangeable sodium, total body water, and total exchangeable potassium. Potassium depletion causes a shift of sodium into cells with a comparable exit of potas­sium from cells into extracellular fluid. The reverse process occurs during potassium repletion, leading to an increase in serum sodium concentration and making hypoka­lemia a risk factor for developing osmotic demyelination syndrome (ODS).⁴

Treating hyponatremia
Hyponatremia treatment depends on its severity, presence or absence of symptoms, and whether the hyponatremia is acute (<24 hours) or chronic (>48 hours).⁵

Because of Mr. W’s extremely low serum sodium concentration, predisposition to hyponatremia secondary to alcoholism, and history of severe hyponatremia, it is likely he is chronically hyponatremic.

In patients with chronic hyponatremia, neurological sequelae are associated with the need for a more rapid rate of correction of serum sodium. For most patients with chronic hyponatremia, a correction rate of ≤10 to 12 mEq/L during the first 24 hours and <18 mEq/L over 48 hours is recom­mended to avoid ODS.⁶

 

Evidence suggests, however, that this 1-day limit might be too high for some patients. Alcoholism, hypokalemia, mal­nutrition, and liver disease are present in a high percentage of patients who develop

ODS after correcting hyponatremia (Table 1).⁶ Therefore, for patients such as Mr. W who are at high risk of ODS, experts recommend a goal of 4 to 6 mEq/L/d with a correction rate of ≤8 mEq/L in any 24-hour period (Table 2).⁶

 

TREATMENT Sodium normalizes
Mr. W receives 1 L of normal saline in the ED before admission to the MICU. Once in the MICU, despite likely chronic hyponatremia, he receives hypertonic (3%) saline, followed by normal saline. Initially, he responds when the serum sodium concentration improves. Because of his likely SIADH, Mr. W is fluid-restricted for 4 days. Serum sodium returns to normal over 7 hospital days (Figure 2). To address the pro­found hypokalemia, Mr. S receives 30 mEq of potassium chloride in the ED, and potas­sium is repeated daily throughout his stay in the MICU.

Mr. W remains lethargic, with intermittent periods of confusion throughout the hospital stay. His altered mental status is attributed to hepatic encephalopathy secondary to alco­holic hepatitis. The Maddrey discriminant function is a calculation that stratifies patients with alcoholic hepatitis for risk of mortal­ity and the use of steroids. Because Mr. W shows a Maddrey discriminant function ≥32, he receives methylprednisolone, followed by pentoxifylline, and liver function tests trend down. He also receives lactulose throughout hospitalization.

By discharge on hospital day 9, Mr. W’s serum sodium is 138 mEq/L; serum potas­sium, 4.1 mEq/L. Total bilirubin and prothrom­bin remain elevated. Mr. W is discharged on lactulose, thiamine, folic acid, and a 1-month course of pentoxifylline, 400 mg, 3 times a day.

READMISSION Unsteady gait, nausea
Three days after discharge, Mr. W returns to the ED after experiencing a 20-second epi­sode of total body rigidity. He has an unsteady gait and worsening nausea and vomiting.

When Mr. W arrives in the ED, he confirms he is taking his discharge medications as pre­scribed. His parents report that he has con­sumed alcohol and Cannabis since discharge and has been taking his sibling’s prescription medications, including quetiapine.

In the ED, Mr. W is awake, alert, and ori­ented to person, place, and time. Vital signs are: pulse, 118 beats per minute; blood pres­sure, 128/73 mm Hg; respirations, 16 breaths per minute; and temperature, 98.5ºF. Physical examination, again, is notable for scleral icterus, jaundice, and asterixis. No focal neu­rologic deficits are noted.

Consistent with Mr. W’s previous admis­sion, laboratory values reveal altered hepatic function and impaired coagulation. The serum sodium level remains within normal limits at 136 mEq/L. However, again, meta­bolic disturbances include decreased chloride (97 mEq/L), potassium (2.9 mEq/L), and CO2 (18.2 mEq/L). CT on readmission is unchanged from the earlier hospitalization.

What is your differential diagnosis for Mr. W’s total body rigidity?
   a) seizure
   b) ODS
   c) drug intoxication
   d) neuroleptic malignant syndrome

EVALUATION Shaking and weakness
Once admitted to the hospital, Mr. W reports an episode of right upper-extremity “shak­ing,” followed by weakness. He remembers the entire event and denies tongue biting or incontinence. He is evaluated for pos­sible seizure, given his multiple risk factors, including drug and alcohol use, ingestion of quetiapine, and history of hyponatremia. Routine EEG is negative but prolactin level is elevated.

Mr. W’s mental status continues to wax and wane, prompting a neurology consult and MRI for further evaluation. MRI of the brain without contrast reveals restricted diffusion in the pons centrally, with extension bilaterally to the midbrain and thalami—findings con­sistent with central pontine myelinolysis. A neurology consultation reveals quadriparesis, paraparesis, dysarthria, and diplopia on exam­ination, all symptoms associated with central pontine myelinolysis.

The authors’ observations
ODS, including central and extrapontine myelinolysis, is a demyelinating condi­tion that occurs because of severe osmotic stress, most commonly secondary to the overly rapid correction of hyponatremia in patients with conditions leading to nutritional or electrolyte stress.⁷ Mr. W is considered at high risk of developing ODS because he fulfills the 5 criteria listed in Table 1.

Several psychiatric illnesses and neu­ropsychiatric medications could lead to hyponatremia. Many studies^8-10 have docu­mented hyponatremia and resulting ODS in patients with alcoholism, schizophrenia, anorexia, primary psychogenic polydipsia, and MDMA (3,4-methylenedioxymetham­phetamine) abuse. Hyponatremia is a side effect of several neuropsychiatric medica­tions, including serotonin reuptake inhibi­tors, lithium, tricyclic antidepressants, opioids, carbamazepine, oxcarbazepine, and antipsychotic polypharmacy. Other commonly used medications associated with hyponatremia include salt-losing diuretics, nonsteroidal anti-inflammatory drugs, and acetaminophen.⁷

Disease severity varies from asymptom­atic to coma or death. Symptoms, although some could reverse completely, typically are a combination of neuropsychiatric (ie, emotional lability, disinhibition, and other bizarre behaviors) and neurologic. Neurologic symptoms include confusion, impaired cognition, dysarthria, dyspha­gia, gait instability, weakness or paralysis, and generalized seizures. Severely affected patients could experience “locked-in syn­drome,” in which they are awake but unable to move or communicate. Also consistent with Mr. W’s case, ODS often presents ini­tially with delirium, seizures, or encepha­lopathy, followed by a lucid interval before symptoms develop.⁷

 

Diagnosis is based on the appearance of demyelinating brain lesions on CT or MRI. MRI is more sensitive than CT; however, even an MRI scan can appear normal for as long as 4 weeks after symptoms appear.⁷ Therefore, an initial negative radiologic study in a high-risk patient who develops neurologic symptoms does not exclude ODS. Earlier detection is possible with dif­fusion-weighted MRI, which is most sensi­tive and can detect lesions within 24 hours of developing symptoms.¹¹ The severity of the lesion does not correlate with severity of symptoms.

Studies reveal a considerable range in prognosis of patients with clinically symp­tomatic ODS. A study of 44 patients with central pontine myelinolysis, of which 42 had chronic alcoholism, reported that 34% had no significant functional deficits at follow-up, 34% had minor neurologic defi­cits, and 31% became dependent on per­sonal help. Outcome did not depend on the extent or severity of neurologic symptoms or the severity of concomitant systemic complications.¹²

Because of its poor prognosis, prevention of ODS is important. Because ODS com­monly is caused by overly rapid correction of hyponatremia, it is necessary to adhere to guidelines for treating chronic hypona­tremia (Table 2). If overcorrection occurs, therapeutic re-lowering of serum sodium can be considered, but has not been validated in controlled trials. Based mainly on case reports that suggest benefit from early re-lowering serum sodium in patients with ODS symptoms, experts recommend the following:  
   • administer desmopressin, 2 to 4 μg, every 8 hours parenterally  
   • replace water orally or as 5% dextrose in water intravenously (3 mL/kg/hr)  
   • check serum sodium hourly until serum is reduced to goal.⁶

Bottom Line

Hyponatremia is the most common electrolyte disorder encountered in practice. Osmotic demyelination syndrome often is preventable, with considerable morbidity and mortality. Psychiatrists should be aware of this condition because it could be an adverse effect of many psychiatric medications and there are some psychiatric illnesses in which hyponatremia is a potential risk. In hyponatremic patients with persistent nonspecific neurologic or neuropsychiatric symptoms and negative CT imaging, additional imaging, such as MRI, is warranted.

Related Resources

• Braun MM, Barstow CH, Pyzocha NJ. Diagnosis and management of sodium disorders: hyponatremia and hypernatremia. Am Fam Physician. 2015;91(5):299-307.
• Vaidya C, Ho W, Freda BJ. Management of hyponatremia: providing treatment and avoiding harm. Cleve Clin J Med. 2010;77(10):715-726.

Drug Brand Names
Carbamazepine • Tegretol
Oxcarbazepine • Trileptal
Desmopressin • Stimate, DDAVP
Lithium • Eskalith, Lithobid
Pentoxifylline • Trental, Pentoxil
Methylprednisolone • Medrol
Quetiapine • Seroquel

Disclosure
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.