Clinical Review

The use of minimally invasive gynecologic surgery (MIGS) has grown rapidly over the past 20 years. MIGS, which includes vaginal hysterectomy and laparoscopic hysterectomy, is safe and has fewer complications and a more rapid recovery period than open abdominal surgery.^1,2 In 2005, the role of MIGS was expanded further when the US Food and Drug Administration (FDA) approved robot-assisted surgery for the performance of gynecologic procedures.³ As knowledge and experience in the safe performance of MIGS progresses, the rates for MIGS procedures have skyrocketed and continue to grow. Between 2007 and 2010, laparoscopic hysterectomy rates rose from 23.5% to 30.5%, while robot-assisted laparoscopic hysterectomy rates increased from 0.5% to 9.5%, representing 40% of all hysterectomies.⁴ Due to the benefits of minimally invasive surgery over open abdominal surgery, patient and physician preference for minimally invasive procedures has grown significantly in popularity.^1,5

Because incisions are small in minimally invasive surgery, surgeons have been challenged with removing large specimens through incisions that are much smaller than the presenting pathology. One approach is to use a specimen retrieval bag for specimen extraction. Once the dissection is completed, the specimen is placed within the retrieval bag for removal, thus minimizing exposure of the specimen and its contents to the abdominopelvic cavity and incision.

The use of specimen retrieval devices has been advocated to prevent infection, avoid spillage into the peritoneal cavity, and minimize the risk of port-site metastases in cases of potentially cancerous specimens. Devices include affordable and readily available products, such as nonpowdered gloves, and commercially produced bags.⁶

While the use of specimen containment systems for tissue extraction has been well described in gynecology, the available systems vary widely in construction, size, durability, and shape, potentially leading to confusion and suboptimal bag selection during surgery.⁷ In this article, we review the most common laparoscopic bags available in the United States, provide an overview of bag characteristics, offer practice guidelines for bag selection, and review bag terminology to highlight important concepts for bag selection.

Controversy spurs change

In April 2014, the FDA warned against the use of power morcellation for specimen removal during minimally invasive surgery, citing a prevalence of 1 in 352 unsuspected uterine sarcomas and 1 in 498 unsuspected uterine leiomyosarcomas among women undergoing hysterectomy or myomectomy for presumed benign leiomyoma.⁸ Since then, the risk of occult uterine sarcomas, including leiomyosarcoma, in women undergoing surgery for benign gynecologic indications has been determined to be much lower.

Nonetheless, the clinical importance of contained specimen removal was clearly highlighted and the role of specimen retrieval bags soared to the forefront. Open power morcellation is no longer commonly practiced, and national societies such as the American Association of Gynecologic Laparoscopists (AAGL), the Society of Gynecologic Oncology (SGO), and the American College of Obstetricians and Gynecologists (ACOG) recommend that containment systems be used for safer specimen retrieval during gynecologic surgery.^9-11 After the specimen is placed inside the containment system (typically a specimen bag), the surgeon may deliver the bag through a vaginal colpotomy or through a slightly extended laparoscopic incision to remove bulky specimens using cold-cutting extraction techniques.^12-15

Continue to: Know the pathology’s characteristics...

In most cases, based on imaging studies and physical examination, surgeons have a good idea of what to expect before proceeding with surgery. The 2 most common characteristics used for surgical planning are the specimen size (dimensions) and the tissue type (solid, cystic, soft tissue, or mixed). The mass size can range from less than 1 cm to larger than a 20-week sized fibroid uterus. Assessing the specimen in 3 dimensions is important. Tissue type also is a consideration, as soft and squishy masses, such as ovarian cysts, are easier to deflate and manipulate within the bag compared with solid or calcified tumors, such as a large fibroid uterus or a large dermoid with solid components.

Specimen shape also is a critical determinant for bag selection. Most specimen retrieval bags are tapered to varying degrees, and some have an irregular shape. Long tubular structures, such as fallopian tubes that are composed of soft tissue, fit easily into most bags regardless of bag shape or extent of bag taper, whereas the round shape of a bulky myoma may render certain bags ineffective even if the bag’s entrance accommodates the greatest diameter of the myoma. Often, a round mass will not fully fit into a bag because there is a poor fit between the mass’s shape and the bag’s shape and taper. (We discuss the concept of a poor “fit” below.) Knowing the pathology before starting a procedure can help optimize bag selection, streamline operative flow, and reduce waste.

Overview of laparoscopic bag characteristics and clinical applications

The TABLE lists the most common laparoscopic bags available for purchase in the United States. Details include the trocar size, manufacturer, product name, mouth diameter, volume, bag shape, construction material, and best clinical application.

The following are terms used to refer to the components of a laparoscopic retrieval bag:

• Mouth diameter: diameter at the entrance of a fully opened bag (FIGURE 1)
• Bag volume: the total volume a bag can accommodate when completely full
• Bag rim: characteristics of the rim of the bag when opened (that is, rigid vs soft rim, complete vs partial rim mechanism to hold the bag open) (FIGURE 2)
• Bag shape: the shape of the bag when it is fully opened (square shaped vs cone shaped vs curved bag shape) (FIGURE 2)
• Bag taper (severity and type): extent the bag is tapered from the rim of the bag’s entrance to the base of the bag; categorized by taper severity (minimal, gradual, or steep taper) and type (continuous taper or curved taper) (FIGURE 3)
• Ball fit: the maximum spherical specimen size that completely fits into a bag and allows it to cinch closed (FIGURE 4)
• Bag strength: durability of a bag when placed on tension during specimen extraction (weak, moderate, or extremely durable).

Continue to: Mouth diameter...

Mouth diameter

Bag manufacturers often differentiate bag sizes by indicating “volume” in milliliters. Bag volume, however, offers little clinical value to surgeons, as pelvic mass dimensions are usually measured in centimeters on imaging. Rather, an important characteristic for bag selection is the diameter of the rim of the bag when it is fully opened—the so-called bag mouth diameter. For a specimen to fit, the 2 dimensions of the specimen must be smaller than the dimensions of the bag entrance.

Notably, the number often linked to the specimen bag—as, for example, in the 10-mm Endo Catch bag (Covidien/Medtronic)— describes the width of the shaft of the bag before it is opened rather than the mouth diameter of the opened bag. The number actually correlates with the trocar size necessary for bag insertion rather than with the specimen size that can fit into the bag. Therefore, a 10-mm Endo Catch bag cannot fit a 10-cm mass, but rather requires a trocar size of 10 mm or greater for insertion of the bag. Fully opened, the mouth diameters of the 10-mm Endo Catch bag are roughly 6 cm x 7 cm, which allows for delivery of a 6-cm mass.

Because 2 bags that use the same trocar size for insertion may have vastly differing bag dimensions, the surgeon must know the bag mouth diameters when selecting a bag to remove the presenting pathology. For example, the Inzii 12 (Applied Medical) laparoscopic bag has mouth diameters of 9.7 cm × 13.0 cm, whereas the Anchor TRSROBO-12 (ConMed) has mouth diameters of 6.7 cm × 7.6 cm (TABLE). Although both bags can be inserted through a 12-mm trocar, both bags cannot fit the same size mass for removal.

Shape and taper

Laparoscopic bags come in various shapes (curved, cone, or square shaped), with varying levels of bag taper (steep, gradual, or no taper) (FIGURES 2 and 3). While taper has little impact on long and skinny specimens, taper may hinder successful bagging of bulky or spherical specimens.

Each bag has different grades of taper regardless of mouth diameter or trocar size. For round masses, the steeper the taper, the smaller the mass that can comfortably fit within the bag. This concept is connected to the idea of “ball fit,” explained below.

In addition, bag shape may affect what mass size can fit into the bag. An irregularly shaped curved bag or a bag with a steep taper may be well suited for removal of multiple specimens of varying sizes or soft masses that are malleable enough to conform to the bag’s shape (such as a ruptured ovarian cyst). Alternatively, a square-shaped bag or a bag with minimal taper would better accommodate a round mass.

Ball fit

When thinking about large circular masses, such as myomas or ovarian cysts, one must consider the ball fit. This refers to the maximum spherical size of the specimen that fits completely within a bag while allowing the bag to cinch closed. Generally, this is an estimation that factors in the bag shape, extent of the bag taper, bag mouth diameter, and specimen shape and tissue type. At times, although a mass can fit through the bag’s mouth diameter, a steep taper may prevent the mass from being fully bagged and limit closure of the bag (FIGURE 4).

Curved bags like the Anchor TRSVATS-15 (ConMed), which have a very narrow bottom, are prone to a limited ball fit, and thus the bag mouth diameter will not correlate with the largest mass size that can be fitted within the bag. Therefore, if using a steeply tapered bag for removal of large round masses, do not rely on the bag’s mouth diameter for bag selection. The surgeon must visualize the ball fit within the bag, taking into account the specimen size and shape, bag shape, and bag taper. In these scenarios, using the diameter of the midportion of the opened bag may better reflect the mass size that can fit into that bag.

Bag strength

Bag strength depends on the material used for bag construction. Most laparoscopic bags in the United States are made of 3 different materials: polyurethane, polypropylene, and ripstop nylon.

Polyurethane and polypropylene are synthetic plastic polymers; in bag form they are stretchy and, under extreme force, may tear. They are best used for bagging fluid-filled cysts or soft pliable masses that will not require extensive bag or tissue handling, such as extraction of large leiomyomas. Polyurethane and polypropylene bags are more susceptible to puncture with sharp laparoscopic instruments or scalpels, and care must be taken to avoid accidentally cutting the bag during tissue extraction.

Alternatively, bags made of ripstop nylon are favored for their bag strength. Ripstop nylon is a synthetic fabric that is woven together in a crosshatch pattern that makes it resistant to tearing and ripping. It was developed originally during World War II as a replacement for silk parachutes. Modern applications include its use in sails, kites, and high-quality camping equipment. This material has a favorable strength-to-weight ratio, and, in case of a tear, it is less prone to extension of the tear. For surgical applications, these bags are best used for bagging specimens that will require a lot of bag manipulation and tissue extraction. However, the ripstop fabric takes up more space in the incision than polyurethane or polypropylene, leaving the surgeon with less space for tissue extraction. Thus, as a tradeoff for bag strength, the surgeon may need to extend the incision a little, and a small self-retracting wound retractor may be necessary to allow visibility for safe tissue extraction when using a ripstop nylon bag compared with others.

Continue to: Trocar selection is important...

Trocar selection is important

While considering bag selection, the surgeon also must consider trocar selection to allow for laparoscopic insertion of the bag. Trocar size for bag selection refers to the minimum trocar diameter needed to insert the laparoscopic bag. Most bags are designed to fit into a laparoscopic trocar or into the skin incision that previously housed the trocar. Trocar size does not directly correlate with bag mouth diameter; for example, a 10-mm laparoscopic bag that can be inserted through a 10- or 12-mm trocar size cannot fit a 10-cm mass (see the mouth diameter section above).

A tip to maximize operating room (OR) efficiency is to start off with a larger trocar, such as a 12-mm trocar, if it is known that a laparoscopic bag with a 12-mm trocar size will be used, rather than starting with a 5-mm trocar and upsizing the port site incision. This saves time and offers intraoperative flexibility, allowing for the use of larger instruments and quicker insufflation.

Furthermore, if the specimen has a solid component and tissue extraction is anticipated, consider starting off with a large trocar, one that is larger than the bag’s trocar size since the incision likely will be extended. For example, even if a myoma will fit within a 10-mm laparoscopic bag made of ripstop nylon, using a 15-mm trocar rather than a 10-mm trocar may be considered since the skin and fascial incisions will need to be extended to allow for cold-cut tissue extraction. Starting with the larger 15-mm trocar may offer surgical advantages, such as direct needle delivery of larger needles for myometrial closure after myomectomy or direct removal of smaller myomas through the trocar to avoid bagging multiple specimens.

Putting it all together

To optimize efficiency in the OR for specimen removal, we recommend streamlining OR flow and reducing waste by first considering the specimen size, tissue type, bag shape, and trocar selection. Choose a bag by taking into account the bag mouth diameter and the amount of taper you will need to obtain an appropriate ball fit. If the tissue type is soft and pliable, consider a polyurethane or polypropylene bag and the smallest bag size possible, even if it has a narrow bag shape and taper.

However, if the tissue type is solid, the shape is round, and the mass is large (requiring extensive tissue extraction for removal), consider a bag made of ripstop nylon and factor in the bag shape as well as the bag taper. Using a bag without a steep taper may allow a better fit.

After choosing a laparoscopic bag, select the appropriate trocars necessary for completion of the surgery. Consider starting off with a larger trocar rather than spending the time to upsize a trocar if you plan to use a large bag or intend to extend the trocar incision for a contained tissue extraction. These tips will help optimize efficiency, reduce equipment wastage, and prevent intra-abdominal spillage.

Keep in mind that all procedures, including specimen removal using containment systems, have inherent risks. For example, visualization of the mass within the bag and visualization of vital structures may be hindered by bulkiness of the bag or specimen. There is also a risk of bag compromise and leakage, whether through manipulation of the bag or puncture during specimen extraction. Lastly, even though removing a specimen within a containment system minimizes spillage and reports of in-bag cold-knife tissue extraction in women with histologically proven endometrial cancer have suggested that it is safe, laparoscopic bags have not been proven to prevent the dissemination of malignant tissue fragments.^16,17

Overall, the inherent risks of specimen extraction during minimally invasive surgery are far outweighed by the well-established advantages of laparoscopic surgery, which carries lower risks of surgical complications such as bleeding and infection, shorter hospital stay, and quicker recovery time compared to laparotomy. There is no doubt minimally invasive surgery offers many benefits.

In summary, for best bag selection, it is equally important to know the characteristics of the pathology as it is to know the features of the specimen retrieval systems available at your institution. Understanding both the pathology and the equipment available will allow the surgeon to make the best surgical decisions for the case. ●

The use of minimally invasive gynecologic surgery (MIGS) has grown rapidly over the past 20 years. MIGS, which includes vaginal hysterectomy and laparoscopic hysterectomy, is safe and has fewer complications and a more rapid recovery period than open abdominal surgery.^1,2 In 2005, the role of MIGS was expanded further when the US Food and Drug Administration (FDA) approved robot-assisted surgery for the performance of gynecologic procedures.³ As knowledge and experience in the safe performance of MIGS progresses, the rates for MIGS procedures have skyrocketed and continue to grow. Between 2007 and 2010, laparoscopic hysterectomy rates rose from 23.5% to 30.5%, while robot-assisted laparoscopic hysterectomy rates increased from 0.5% to 9.5%, representing 40% of all hysterectomies.⁴ Due to the benefits of minimally invasive surgery over open abdominal surgery, patient and physician preference for minimally invasive procedures has grown significantly in popularity.^1,5

Because incisions are small in minimally invasive surgery, surgeons have been challenged with removing large specimens through incisions that are much smaller than the presenting pathology. One approach is to use a specimen retrieval bag for specimen extraction. Once the dissection is completed, the specimen is placed within the retrieval bag for removal, thus minimizing exposure of the specimen and its contents to the abdominopelvic cavity and incision.

The use of specimen retrieval devices has been advocated to prevent infection, avoid spillage into the peritoneal cavity, and minimize the risk of port-site metastases in cases of potentially cancerous specimens. Devices include affordable and readily available products, such as nonpowdered gloves, and commercially produced bags.⁶

While the use of specimen containment systems for tissue extraction has been well described in gynecology, the available systems vary widely in construction, size, durability, and shape, potentially leading to confusion and suboptimal bag selection during surgery.⁷ In this article, we review the most common laparoscopic bags available in the United States, provide an overview of bag characteristics, offer practice guidelines for bag selection, and review bag terminology to highlight important concepts for bag selection.

Controversy spurs change

In April 2014, the FDA warned against the use of power morcellation for specimen removal during minimally invasive surgery, citing a prevalence of 1 in 352 unsuspected uterine sarcomas and 1 in 498 unsuspected uterine leiomyosarcomas among women undergoing hysterectomy or myomectomy for presumed benign leiomyoma.⁸ Since then, the risk of occult uterine sarcomas, including leiomyosarcoma, in women undergoing surgery for benign gynecologic indications has been determined to be much lower.

Nonetheless, the clinical importance of contained specimen removal was clearly highlighted and the role of specimen retrieval bags soared to the forefront. Open power morcellation is no longer commonly practiced, and national societies such as the American Association of Gynecologic Laparoscopists (AAGL), the Society of Gynecologic Oncology (SGO), and the American College of Obstetricians and Gynecologists (ACOG) recommend that containment systems be used for safer specimen retrieval during gynecologic surgery.^9-11 After the specimen is placed inside the containment system (typically a specimen bag), the surgeon may deliver the bag through a vaginal colpotomy or through a slightly extended laparoscopic incision to remove bulky specimens using cold-cutting extraction techniques.^12-15

Continue to: Know the pathology’s characteristics...

In most cases, based on imaging studies and physical examination, surgeons have a good idea of what to expect before proceeding with surgery. The 2 most common characteristics used for surgical planning are the specimen size (dimensions) and the tissue type (solid, cystic, soft tissue, or mixed). The mass size can range from less than 1 cm to larger than a 20-week sized fibroid uterus. Assessing the specimen in 3 dimensions is important. Tissue type also is a consideration, as soft and squishy masses, such as ovarian cysts, are easier to deflate and manipulate within the bag compared with solid or calcified tumors, such as a large fibroid uterus or a large dermoid with solid components.

Specimen shape also is a critical determinant for bag selection. Most specimen retrieval bags are tapered to varying degrees, and some have an irregular shape. Long tubular structures, such as fallopian tubes that are composed of soft tissue, fit easily into most bags regardless of bag shape or extent of bag taper, whereas the round shape of a bulky myoma may render certain bags ineffective even if the bag’s entrance accommodates the greatest diameter of the myoma. Often, a round mass will not fully fit into a bag because there is a poor fit between the mass’s shape and the bag’s shape and taper. (We discuss the concept of a poor “fit” below.) Knowing the pathology before starting a procedure can help optimize bag selection, streamline operative flow, and reduce waste.

Overview of laparoscopic bag characteristics and clinical applications

The TABLE lists the most common laparoscopic bags available for purchase in the United States. Details include the trocar size, manufacturer, product name, mouth diameter, volume, bag shape, construction material, and best clinical application.

The following are terms used to refer to the components of a laparoscopic retrieval bag:

• Mouth diameter: diameter at the entrance of a fully opened bag (FIGURE 1)
• Bag volume: the total volume a bag can accommodate when completely full
• Bag rim: characteristics of the rim of the bag when opened (that is, rigid vs soft rim, complete vs partial rim mechanism to hold the bag open) (FIGURE 2)
• Bag shape: the shape of the bag when it is fully opened (square shaped vs cone shaped vs curved bag shape) (FIGURE 2)
• Bag taper (severity and type): extent the bag is tapered from the rim of the bag’s entrance to the base of the bag; categorized by taper severity (minimal, gradual, or steep taper) and type (continuous taper or curved taper) (FIGURE 3)
• Ball fit: the maximum spherical specimen size that completely fits into a bag and allows it to cinch closed (FIGURE 4)
• Bag strength: durability of a bag when placed on tension during specimen extraction (weak, moderate, or extremely durable).

Continue to: Mouth diameter...

Mouth diameter

Bag manufacturers often differentiate bag sizes by indicating “volume” in milliliters. Bag volume, however, offers little clinical value to surgeons, as pelvic mass dimensions are usually measured in centimeters on imaging. Rather, an important characteristic for bag selection is the diameter of the rim of the bag when it is fully opened—the so-called bag mouth diameter. For a specimen to fit, the 2 dimensions of the specimen must be smaller than the dimensions of the bag entrance.

Notably, the number often linked to the specimen bag—as, for example, in the 10-mm Endo Catch bag (Covidien/Medtronic)— describes the width of the shaft of the bag before it is opened rather than the mouth diameter of the opened bag. The number actually correlates with the trocar size necessary for bag insertion rather than with the specimen size that can fit into the bag. Therefore, a 10-mm Endo Catch bag cannot fit a 10-cm mass, but rather requires a trocar size of 10 mm or greater for insertion of the bag. Fully opened, the mouth diameters of the 10-mm Endo Catch bag are roughly 6 cm x 7 cm, which allows for delivery of a 6-cm mass.

Because 2 bags that use the same trocar size for insertion may have vastly differing bag dimensions, the surgeon must know the bag mouth diameters when selecting a bag to remove the presenting pathology. For example, the Inzii 12 (Applied Medical) laparoscopic bag has mouth diameters of 9.7 cm × 13.0 cm, whereas the Anchor TRSROBO-12 (ConMed) has mouth diameters of 6.7 cm × 7.6 cm (TABLE). Although both bags can be inserted through a 12-mm trocar, both bags cannot fit the same size mass for removal.

Shape and taper

Laparoscopic bags come in various shapes (curved, cone, or square shaped), with varying levels of bag taper (steep, gradual, or no taper) (FIGURES 2 and 3). While taper has little impact on long and skinny specimens, taper may hinder successful bagging of bulky or spherical specimens.

Each bag has different grades of taper regardless of mouth diameter or trocar size. For round masses, the steeper the taper, the smaller the mass that can comfortably fit within the bag. This concept is connected to the idea of “ball fit,” explained below.

In addition, bag shape may affect what mass size can fit into the bag. An irregularly shaped curved bag or a bag with a steep taper may be well suited for removal of multiple specimens of varying sizes or soft masses that are malleable enough to conform to the bag’s shape (such as a ruptured ovarian cyst). Alternatively, a square-shaped bag or a bag with minimal taper would better accommodate a round mass.

Ball fit

When thinking about large circular masses, such as myomas or ovarian cysts, one must consider the ball fit. This refers to the maximum spherical size of the specimen that fits completely within a bag while allowing the bag to cinch closed. Generally, this is an estimation that factors in the bag shape, extent of the bag taper, bag mouth diameter, and specimen shape and tissue type. At times, although a mass can fit through the bag’s mouth diameter, a steep taper may prevent the mass from being fully bagged and limit closure of the bag (FIGURE 4).

Curved bags like the Anchor TRSVATS-15 (ConMed), which have a very narrow bottom, are prone to a limited ball fit, and thus the bag mouth diameter will not correlate with the largest mass size that can be fitted within the bag. Therefore, if using a steeply tapered bag for removal of large round masses, do not rely on the bag’s mouth diameter for bag selection. The surgeon must visualize the ball fit within the bag, taking into account the specimen size and shape, bag shape, and bag taper. In these scenarios, using the diameter of the midportion of the opened bag may better reflect the mass size that can fit into that bag.

Bag strength

Bag strength depends on the material used for bag construction. Most laparoscopic bags in the United States are made of 3 different materials: polyurethane, polypropylene, and ripstop nylon.

Polyurethane and polypropylene are synthetic plastic polymers; in bag form they are stretchy and, under extreme force, may tear. They are best used for bagging fluid-filled cysts or soft pliable masses that will not require extensive bag or tissue handling, such as extraction of large leiomyomas. Polyurethane and polypropylene bags are more susceptible to puncture with sharp laparoscopic instruments or scalpels, and care must be taken to avoid accidentally cutting the bag during tissue extraction.

Alternatively, bags made of ripstop nylon are favored for their bag strength. Ripstop nylon is a synthetic fabric that is woven together in a crosshatch pattern that makes it resistant to tearing and ripping. It was developed originally during World War II as a replacement for silk parachutes. Modern applications include its use in sails, kites, and high-quality camping equipment. This material has a favorable strength-to-weight ratio, and, in case of a tear, it is less prone to extension of the tear. For surgical applications, these bags are best used for bagging specimens that will require a lot of bag manipulation and tissue extraction. However, the ripstop fabric takes up more space in the incision than polyurethane or polypropylene, leaving the surgeon with less space for tissue extraction. Thus, as a tradeoff for bag strength, the surgeon may need to extend the incision a little, and a small self-retracting wound retractor may be necessary to allow visibility for safe tissue extraction when using a ripstop nylon bag compared with others.

Continue to: Trocar selection is important...

Trocar selection is important

While considering bag selection, the surgeon also must consider trocar selection to allow for laparoscopic insertion of the bag. Trocar size for bag selection refers to the minimum trocar diameter needed to insert the laparoscopic bag. Most bags are designed to fit into a laparoscopic trocar or into the skin incision that previously housed the trocar. Trocar size does not directly correlate with bag mouth diameter; for example, a 10-mm laparoscopic bag that can be inserted through a 10- or 12-mm trocar size cannot fit a 10-cm mass (see the mouth diameter section above).

A tip to maximize operating room (OR) efficiency is to start off with a larger trocar, such as a 12-mm trocar, if it is known that a laparoscopic bag with a 12-mm trocar size will be used, rather than starting with a 5-mm trocar and upsizing the port site incision. This saves time and offers intraoperative flexibility, allowing for the use of larger instruments and quicker insufflation.

Furthermore, if the specimen has a solid component and tissue extraction is anticipated, consider starting off with a large trocar, one that is larger than the bag’s trocar size since the incision likely will be extended. For example, even if a myoma will fit within a 10-mm laparoscopic bag made of ripstop nylon, using a 15-mm trocar rather than a 10-mm trocar may be considered since the skin and fascial incisions will need to be extended to allow for cold-cut tissue extraction. Starting with the larger 15-mm trocar may offer surgical advantages, such as direct needle delivery of larger needles for myometrial closure after myomectomy or direct removal of smaller myomas through the trocar to avoid bagging multiple specimens.

Putting it all together

To optimize efficiency in the OR for specimen removal, we recommend streamlining OR flow and reducing waste by first considering the specimen size, tissue type, bag shape, and trocar selection. Choose a bag by taking into account the bag mouth diameter and the amount of taper you will need to obtain an appropriate ball fit. If the tissue type is soft and pliable, consider a polyurethane or polypropylene bag and the smallest bag size possible, even if it has a narrow bag shape and taper.

However, if the tissue type is solid, the shape is round, and the mass is large (requiring extensive tissue extraction for removal), consider a bag made of ripstop nylon and factor in the bag shape as well as the bag taper. Using a bag without a steep taper may allow a better fit.

After choosing a laparoscopic bag, select the appropriate trocars necessary for completion of the surgery. Consider starting off with a larger trocar rather than spending the time to upsize a trocar if you plan to use a large bag or intend to extend the trocar incision for a contained tissue extraction. These tips will help optimize efficiency, reduce equipment wastage, and prevent intra-abdominal spillage.

Keep in mind that all procedures, including specimen removal using containment systems, have inherent risks. For example, visualization of the mass within the bag and visualization of vital structures may be hindered by bulkiness of the bag or specimen. There is also a risk of bag compromise and leakage, whether through manipulation of the bag or puncture during specimen extraction. Lastly, even though removing a specimen within a containment system minimizes spillage and reports of in-bag cold-knife tissue extraction in women with histologically proven endometrial cancer have suggested that it is safe, laparoscopic bags have not been proven to prevent the dissemination of malignant tissue fragments.^16,17

Overall, the inherent risks of specimen extraction during minimally invasive surgery are far outweighed by the well-established advantages of laparoscopic surgery, which carries lower risks of surgical complications such as bleeding and infection, shorter hospital stay, and quicker recovery time compared to laparotomy. There is no doubt minimally invasive surgery offers many benefits.

In summary, for best bag selection, it is equally important to know the characteristics of the pathology as it is to know the features of the specimen retrieval systems available at your institution. Understanding both the pathology and the equipment available will allow the surgeon to make the best surgical decisions for the case. ●

The use of minimally invasive gynecologic surgery (MIGS) has grown rapidly over the past 20 years. MIGS, which includes vaginal hysterectomy and laparoscopic hysterectomy, is safe and has fewer complications and a more rapid recovery period than open abdominal surgery.^1,2 In 2005, the role of MIGS was expanded further when the US Food and Drug Administration (FDA) approved robot-assisted surgery for the performance of gynecologic procedures.³ As knowledge and experience in the safe performance of MIGS progresses, the rates for MIGS procedures have skyrocketed and continue to grow. Between 2007 and 2010, laparoscopic hysterectomy rates rose from 23.5% to 30.5%, while robot-assisted laparoscopic hysterectomy rates increased from 0.5% to 9.5%, representing 40% of all hysterectomies.⁴ Due to the benefits of minimally invasive surgery over open abdominal surgery, patient and physician preference for minimally invasive procedures has grown significantly in popularity.^1,5

Because incisions are small in minimally invasive surgery, surgeons have been challenged with removing large specimens through incisions that are much smaller than the presenting pathology. One approach is to use a specimen retrieval bag for specimen extraction. Once the dissection is completed, the specimen is placed within the retrieval bag for removal, thus minimizing exposure of the specimen and its contents to the abdominopelvic cavity and incision.

The use of specimen retrieval devices has been advocated to prevent infection, avoid spillage into the peritoneal cavity, and minimize the risk of port-site metastases in cases of potentially cancerous specimens. Devices include affordable and readily available products, such as nonpowdered gloves, and commercially produced bags.⁶

While the use of specimen containment systems for tissue extraction has been well described in gynecology, the available systems vary widely in construction, size, durability, and shape, potentially leading to confusion and suboptimal bag selection during surgery.⁷ In this article, we review the most common laparoscopic bags available in the United States, provide an overview of bag characteristics, offer practice guidelines for bag selection, and review bag terminology to highlight important concepts for bag selection.

Controversy spurs change

In April 2014, the FDA warned against the use of power morcellation for specimen removal during minimally invasive surgery, citing a prevalence of 1 in 352 unsuspected uterine sarcomas and 1 in 498 unsuspected uterine leiomyosarcomas among women undergoing hysterectomy or myomectomy for presumed benign leiomyoma.⁸ Since then, the risk of occult uterine sarcomas, including leiomyosarcoma, in women undergoing surgery for benign gynecologic indications has been determined to be much lower.

Nonetheless, the clinical importance of contained specimen removal was clearly highlighted and the role of specimen retrieval bags soared to the forefront. Open power morcellation is no longer commonly practiced, and national societies such as the American Association of Gynecologic Laparoscopists (AAGL), the Society of Gynecologic Oncology (SGO), and the American College of Obstetricians and Gynecologists (ACOG) recommend that containment systems be used for safer specimen retrieval during gynecologic surgery.^9-11 After the specimen is placed inside the containment system (typically a specimen bag), the surgeon may deliver the bag through a vaginal colpotomy or through a slightly extended laparoscopic incision to remove bulky specimens using cold-cutting extraction techniques.^12-15

Continue to: Know the pathology’s characteristics...

In most cases, based on imaging studies and physical examination, surgeons have a good idea of what to expect before proceeding with surgery. The 2 most common characteristics used for surgical planning are the specimen size (dimensions) and the tissue type (solid, cystic, soft tissue, or mixed). The mass size can range from less than 1 cm to larger than a 20-week sized fibroid uterus. Assessing the specimen in 3 dimensions is important. Tissue type also is a consideration, as soft and squishy masses, such as ovarian cysts, are easier to deflate and manipulate within the bag compared with solid or calcified tumors, such as a large fibroid uterus or a large dermoid with solid components.

Specimen shape also is a critical determinant for bag selection. Most specimen retrieval bags are tapered to varying degrees, and some have an irregular shape. Long tubular structures, such as fallopian tubes that are composed of soft tissue, fit easily into most bags regardless of bag shape or extent of bag taper, whereas the round shape of a bulky myoma may render certain bags ineffective even if the bag’s entrance accommodates the greatest diameter of the myoma. Often, a round mass will not fully fit into a bag because there is a poor fit between the mass’s shape and the bag’s shape and taper. (We discuss the concept of a poor “fit” below.) Knowing the pathology before starting a procedure can help optimize bag selection, streamline operative flow, and reduce waste.

Overview of laparoscopic bag characteristics and clinical applications

The TABLE lists the most common laparoscopic bags available for purchase in the United States. Details include the trocar size, manufacturer, product name, mouth diameter, volume, bag shape, construction material, and best clinical application.

The following are terms used to refer to the components of a laparoscopic retrieval bag:

• Mouth diameter: diameter at the entrance of a fully opened bag (FIGURE 1)
• Bag volume: the total volume a bag can accommodate when completely full
• Bag rim: characteristics of the rim of the bag when opened (that is, rigid vs soft rim, complete vs partial rim mechanism to hold the bag open) (FIGURE 2)
• Bag shape: the shape of the bag when it is fully opened (square shaped vs cone shaped vs curved bag shape) (FIGURE 2)
• Bag taper (severity and type): extent the bag is tapered from the rim of the bag’s entrance to the base of the bag; categorized by taper severity (minimal, gradual, or steep taper) and type (continuous taper or curved taper) (FIGURE 3)
• Ball fit: the maximum spherical specimen size that completely fits into a bag and allows it to cinch closed (FIGURE 4)
• Bag strength: durability of a bag when placed on tension during specimen extraction (weak, moderate, or extremely durable).

Continue to: Mouth diameter...

Mouth diameter

Bag manufacturers often differentiate bag sizes by indicating “volume” in milliliters. Bag volume, however, offers little clinical value to surgeons, as pelvic mass dimensions are usually measured in centimeters on imaging. Rather, an important characteristic for bag selection is the diameter of the rim of the bag when it is fully opened—the so-called bag mouth diameter. For a specimen to fit, the 2 dimensions of the specimen must be smaller than the dimensions of the bag entrance.

Notably, the number often linked to the specimen bag—as, for example, in the 10-mm Endo Catch bag (Covidien/Medtronic)— describes the width of the shaft of the bag before it is opened rather than the mouth diameter of the opened bag. The number actually correlates with the trocar size necessary for bag insertion rather than with the specimen size that can fit into the bag. Therefore, a 10-mm Endo Catch bag cannot fit a 10-cm mass, but rather requires a trocar size of 10 mm or greater for insertion of the bag. Fully opened, the mouth diameters of the 10-mm Endo Catch bag are roughly 6 cm x 7 cm, which allows for delivery of a 6-cm mass.

Because 2 bags that use the same trocar size for insertion may have vastly differing bag dimensions, the surgeon must know the bag mouth diameters when selecting a bag to remove the presenting pathology. For example, the Inzii 12 (Applied Medical) laparoscopic bag has mouth diameters of 9.7 cm × 13.0 cm, whereas the Anchor TRSROBO-12 (ConMed) has mouth diameters of 6.7 cm × 7.6 cm (TABLE). Although both bags can be inserted through a 12-mm trocar, both bags cannot fit the same size mass for removal.

Shape and taper

Laparoscopic bags come in various shapes (curved, cone, or square shaped), with varying levels of bag taper (steep, gradual, or no taper) (FIGURES 2 and 3). While taper has little impact on long and skinny specimens, taper may hinder successful bagging of bulky or spherical specimens.

Each bag has different grades of taper regardless of mouth diameter or trocar size. For round masses, the steeper the taper, the smaller the mass that can comfortably fit within the bag. This concept is connected to the idea of “ball fit,” explained below.

In addition, bag shape may affect what mass size can fit into the bag. An irregularly shaped curved bag or a bag with a steep taper may be well suited for removal of multiple specimens of varying sizes or soft masses that are malleable enough to conform to the bag’s shape (such as a ruptured ovarian cyst). Alternatively, a square-shaped bag or a bag with minimal taper would better accommodate a round mass.

Ball fit

When thinking about large circular masses, such as myomas or ovarian cysts, one must consider the ball fit. This refers to the maximum spherical size of the specimen that fits completely within a bag while allowing the bag to cinch closed. Generally, this is an estimation that factors in the bag shape, extent of the bag taper, bag mouth diameter, and specimen shape and tissue type. At times, although a mass can fit through the bag’s mouth diameter, a steep taper may prevent the mass from being fully bagged and limit closure of the bag (FIGURE 4).

Curved bags like the Anchor TRSVATS-15 (ConMed), which have a very narrow bottom, are prone to a limited ball fit, and thus the bag mouth diameter will not correlate with the largest mass size that can be fitted within the bag. Therefore, if using a steeply tapered bag for removal of large round masses, do not rely on the bag’s mouth diameter for bag selection. The surgeon must visualize the ball fit within the bag, taking into account the specimen size and shape, bag shape, and bag taper. In these scenarios, using the diameter of the midportion of the opened bag may better reflect the mass size that can fit into that bag.

Bag strength

Bag strength depends on the material used for bag construction. Most laparoscopic bags in the United States are made of 3 different materials: polyurethane, polypropylene, and ripstop nylon.

Polyurethane and polypropylene are synthetic plastic polymers; in bag form they are stretchy and, under extreme force, may tear. They are best used for bagging fluid-filled cysts or soft pliable masses that will not require extensive bag or tissue handling, such as extraction of large leiomyomas. Polyurethane and polypropylene bags are more susceptible to puncture with sharp laparoscopic instruments or scalpels, and care must be taken to avoid accidentally cutting the bag during tissue extraction.

Alternatively, bags made of ripstop nylon are favored for their bag strength. Ripstop nylon is a synthetic fabric that is woven together in a crosshatch pattern that makes it resistant to tearing and ripping. It was developed originally during World War II as a replacement for silk parachutes. Modern applications include its use in sails, kites, and high-quality camping equipment. This material has a favorable strength-to-weight ratio, and, in case of a tear, it is less prone to extension of the tear. For surgical applications, these bags are best used for bagging specimens that will require a lot of bag manipulation and tissue extraction. However, the ripstop fabric takes up more space in the incision than polyurethane or polypropylene, leaving the surgeon with less space for tissue extraction. Thus, as a tradeoff for bag strength, the surgeon may need to extend the incision a little, and a small self-retracting wound retractor may be necessary to allow visibility for safe tissue extraction when using a ripstop nylon bag compared with others.

Continue to: Trocar selection is important...

Trocar selection is important

While considering bag selection, the surgeon also must consider trocar selection to allow for laparoscopic insertion of the bag. Trocar size for bag selection refers to the minimum trocar diameter needed to insert the laparoscopic bag. Most bags are designed to fit into a laparoscopic trocar or into the skin incision that previously housed the trocar. Trocar size does not directly correlate with bag mouth diameter; for example, a 10-mm laparoscopic bag that can be inserted through a 10- or 12-mm trocar size cannot fit a 10-cm mass (see the mouth diameter section above).

A tip to maximize operating room (OR) efficiency is to start off with a larger trocar, such as a 12-mm trocar, if it is known that a laparoscopic bag with a 12-mm trocar size will be used, rather than starting with a 5-mm trocar and upsizing the port site incision. This saves time and offers intraoperative flexibility, allowing for the use of larger instruments and quicker insufflation.

Furthermore, if the specimen has a solid component and tissue extraction is anticipated, consider starting off with a large trocar, one that is larger than the bag’s trocar size since the incision likely will be extended. For example, even if a myoma will fit within a 10-mm laparoscopic bag made of ripstop nylon, using a 15-mm trocar rather than a 10-mm trocar may be considered since the skin and fascial incisions will need to be extended to allow for cold-cut tissue extraction. Starting with the larger 15-mm trocar may offer surgical advantages, such as direct needle delivery of larger needles for myometrial closure after myomectomy or direct removal of smaller myomas through the trocar to avoid bagging multiple specimens.

Putting it all together

To optimize efficiency in the OR for specimen removal, we recommend streamlining OR flow and reducing waste by first considering the specimen size, tissue type, bag shape, and trocar selection. Choose a bag by taking into account the bag mouth diameter and the amount of taper you will need to obtain an appropriate ball fit. If the tissue type is soft and pliable, consider a polyurethane or polypropylene bag and the smallest bag size possible, even if it has a narrow bag shape and taper.

However, if the tissue type is solid, the shape is round, and the mass is large (requiring extensive tissue extraction for removal), consider a bag made of ripstop nylon and factor in the bag shape as well as the bag taper. Using a bag without a steep taper may allow a better fit.

After choosing a laparoscopic bag, select the appropriate trocars necessary for completion of the surgery. Consider starting off with a larger trocar rather than spending the time to upsize a trocar if you plan to use a large bag or intend to extend the trocar incision for a contained tissue extraction. These tips will help optimize efficiency, reduce equipment wastage, and prevent intra-abdominal spillage.

Keep in mind that all procedures, including specimen removal using containment systems, have inherent risks. For example, visualization of the mass within the bag and visualization of vital structures may be hindered by bulkiness of the bag or specimen. There is also a risk of bag compromise and leakage, whether through manipulation of the bag or puncture during specimen extraction. Lastly, even though removing a specimen within a containment system minimizes spillage and reports of in-bag cold-knife tissue extraction in women with histologically proven endometrial cancer have suggested that it is safe, laparoscopic bags have not been proven to prevent the dissemination of malignant tissue fragments.^16,17

Overall, the inherent risks of specimen extraction during minimally invasive surgery are far outweighed by the well-established advantages of laparoscopic surgery, which carries lower risks of surgical complications such as bleeding and infection, shorter hospital stay, and quicker recovery time compared to laparotomy. There is no doubt minimally invasive surgery offers many benefits.

In summary, for best bag selection, it is equally important to know the characteristics of the pathology as it is to know the features of the specimen retrieval systems available at your institution. Understanding both the pathology and the equipment available will allow the surgeon to make the best surgical decisions for the case. ●

A vaginal ring that can be reused for up to 1 year and a progestin-only pill (POP) with a wider window for missed pills are 2 of the novel contraceptive products introduced to the market this year. In addition, an ongoing study of the levonorgestrel 52-mg intrauterine system (IUS) continues to provide evidence on its extended duration of use, now approved through 6 years.

The segesterone acetate (SA) and ethinyl estradiol (EE) vaginal ring (Annovera) is new among contraceptive options. Segesterone acetate is a novel progestin that can be used only via nonoral routes; it binds specifically to progesterone receptors without estrogenic or antiandrogen effects.¹ Unlike the etonogestrel and ethinyl estradiol ring (NuvaRing; for which generic products became available this past year), which is used for 1 cycle and then thrown away, the SA/EE ring is effective for 13 consecutive cycles. It does not require refrigeration when not in use.² Because a single ring can be used for 13 cycles, users in locations without laws that mandate a 12-month supply of pills, patches, and rings need less frequent visits to the pharmacy or clinic.

Progestin-only contraceptive pills are an important option for patients who desire hormonal contraception and have contraindications to estrogen, such as migraines with aura, cardiovascular risk factors, and being in the early postpartum period.³ In the United States, current POPs contain norethindrone, which has a 3-hour window for missed pills⁴; a desogestrel-only pill available outside the United States has a 12-hour window.⁵ Both are provided as a 28-day pill pack for continuous use, and both result in undesirable bleeding patterns in some users.

The prolonged half-life of drospirenone, another progestin, gives it the potential to increase reliability in the setting of missed or delayed pills and improve bleeding patterns. A new POP contraceptive contains drospirenone (Slynd) and is available in a 28-day pack with a 24-day supply of hormone and a 4-day supply of placebo; it provides a window for missed pill use similar to that for combined hormonal contraception (CHC) as well as a placebo period for a timed withdrawal bleed.^6,7

Liletta is a well-known levonorgestrel 52-mg IUS that was first approved by the US Food and Drug Administration (FDA) in 2015. An ongoing clinical trial has been the basis for approval of this IUS for use in increasing durations, from 3 years initially to 4 and then 5 years. The newest data indicate efficacy up to 6 years.⁸

Continue to: Combined hormonal vaginal system provides a year's contraception with an acceptable safety profile...

Combined hormonal vaginal system provides a year's contraception with an acceptable safety profile 

Archer DF, Merkatz RB, Bahamondes L, et al. Efficacy of the 1-year (13-cycle) segesterone acetate and ethinylestradiol contraceptive vaginal system: results of two multicentre, open-label, single-arm, phase 3 trials. Lancet Glob Health. 2019;7:e1054-e1064. 

Gemzell-Danielsson K, Sitruk-Ware R, Creinin MD, et al. Segesterone acetate/ethinyl estradiol 12-month contraceptive vaginal system safety evaluation. Contraception. 2019;99:323-328. 

Archer and colleagues reported the results of 2 pivotal multicenter, open-label, phase 3 trials, which included 2,265 users, conducted to evaluate efficacy and return to menses or pregnancy after use of the 1-year (13 cycles) SA/EE contraceptive vaginal system (CVS). 

Details of the efficacy study 

The study included 1,130 women in a US-only study and 1,135 women in an international study with sites in the United States, Australia, Brazil, Chile, Dominican Republic, Finland, Hungary, and Sweden. Participants used the CVS for 21 days followed by a 7-day use-free interval for up to 13 consecutive cycles; they were instructed not to remove the CVS for more than 2 hours during the 21 days of use. 

Primary and secondary efficacy outcomes were calculated using the Pearl Index and an intention-to-treat Kaplan-Meier life table, respectively. At the end of the study, users who desired not to continue hormonal contraception or to become pregnant were followed up for 6 months to evaluate return to menses or pregnancy. 

Year-long effectiveness 

The investigators reported an overall Pearl index of 2.98 (95% confidence interval [CI], 2.13-4.06) and a Kaplan-Meier life table cumulative efficacy rate of 97.5% (FIGURE 1), consistent with other recently approved CHC methods. Women from non-European sites, who primarily were US participants, had a Pearl Index of 3.25 (95% CI, 2.35-4.37), and participants from the European sites had a Pearl Index of 0.47 (95% CI, 0.03-2.07). Importantly, CVS removal had a significant impact on efficacy, with a Pearl Index of 5.98 (95% CI, 2.46-9.27) in users reporting CVS removals for longer than 2 hours, suggesting escape ovulation with improper use. The Pearl Index was highest in users aged 18 to 19 years and was not affected by body mass index (BMI), although 91% of users had a BMI of 29.0 kg/m² or lower. 

There was no trend for a change in pregnancy risk across 13 cycles, providing evidence of CVS efficacy throughout a full year's use. The follow-up portion of the study included 290 users who were not continuing hormonal contraception at study end; all follow-up participants reported return to menses after method discontinuation. 

Clinical safety data 

To evaluate safety outcomes from clinical studies on the CVS containing SA/EE, Gemzell-Danielsson and colleagues analyzed 9 studies. Most of the data were derived from 2 phase 3, multicenter trials (as discussed above), with supporting evidence from 7 other studies. 

Adverse events reported 

Among 2,308 CVS users in the phase 3 trials, 87% reported at least 1 adverse effect, with most of mild or moderate severity. These included headache, 26%; nausea, 18%; vaginal discharge, 10%; and metrorrhagia, 7%. Overall, 12% of CVS users discontinued use due to an adverse effect. Two percent of users experienced severe adverse effects, including venous thromboembolism (VTE), allergic reaction, gallbladder disease, and spontaneous abortion. 

In the US-only phase 3 trial, 2 VTE events occurred in the first 6 months in women with baseline BMI greater than 29.0 kg/m²; therefore, enrollment of patients with a BMI greater than 29.0 kg/m² was halted and current users meeting that criteria were discontinued. Notably, no cases of VTE occurred in studies with a segesterone acetate-only CVS; this suggests that risk can be attributed to the estrogen component. Overall, 4 nonfatal VTEs occurred, all among the 1,536 women enrolled in the phase 3 trials (4 of 1,536 [0.3%]); at least 3 of these cases occurred in users with VTE risk factors (TABLE 1). The estimated VTE rate in CVS users with a BMI greater than 29.0 kg/m2 is 10.8/10,000 women-years (95% CI, 8.9-13.1). 

Complete expulsion of the CVS occurred in 7% of cycles and partial expulsion in 19.5% of cycles; users reported expulsion more frequently in the first cycle, most (about 70%) of which were partial expulsions. Of the laboratory values and vital signs studied, including weight, users had no clinically relevant changes from baseline.

Continue to: New drospirenone pill is an effective POP option...

New drospirenone pill is an effective POP option 

Kimble T, Burke AE, Barnhart KT, et al. A 1-year prospective, open-label, single-arm, multicenter, phase 3 trial of the contraceptive efficacy and safety of the oral progestin-only pill drospirenone 4 mg using a 24/4-day regimen. Contracept X. 2020;2:100020. 

Palacios S, Colli E, Regidor PA. Multicenter, phase III trials on the contraceptive efficacy, tolerability and safety of a new drospirenone-only pill. Acta Obstet Gynecol Scand. 2019;98:1549-1557. 

In a prospective, single-arm, multicenter phase 3 trial in the United States, Kimble and colleagues evaluated the efficacy and safety of an oral drospirenone POP in a cyclic 24-day hormone/4-day placebo regimen. The trial included 1,006 users. No BMI cutoff was used, and about one-third of study participants were obese (BMI >30.0 kg/m²). Women were instructed to take a missed tablet as soon as remembered if within 24 hours or with the next scheduled dose if more than 24 hours late. 

Contraceptive effectiveness 

The Pearl Index for nonbreastfeeding users aged 35 years or younger with pregnancies confirmed by a quantitative serum ß-human chorionic gonadotropin test (915 users) was 2.9 (95% CI, 1.5-5.1). Of note, 2 out of 15 on-treatment pregnancies were excluded from this calculation because of protocol site violations, as were 3 pregnancies that were unconfirmed. In the modified full analysis set of 915 users, 36% were obese (BMI≥30 kg/m²), and the Pearl Index was noted to be unaffected by BMI (TABLE 2). 

While 61% of women reported adverse effects, more than 95% of these were mild or moderate in intensity, including headache, nausea, dysmenorrhea, metrorrhagia, and breast pain. No VTE occurred. The frequency of hyperkalemia was 0.5%, and there was no evidence of hypotension, which is significant due to the antimineralocorticoid activity of drospirenone. All cases of hyperkalemia were considered mild, and all women were asymptomatic. There were no clinically relevant changes in body weight, gynecologic exam, or other laboratory values. 

With increased cycles of use, the number of days with bleeding or spotting generally decreased and amenorrhea increased. However, in cycles 11 to 13, 41.6% of users still had unscheduled bleeding (reduced from 57.0% at cycles 2-4), and 29.0% had scheduled bleeding (decreased from 44% at cycles 2-4) (FIGURE 2). With these bleeding patterns, 86.2% of users agreed or strongly agreed that they were satisfied with the product. 

European multicenter study of drospironene 

In a European investigation, Palacios and colleagues pooled and analyzed data from 2 phase 3 multicenter trials to assess the efficacy, tolerability, and safety of the same drospirenone-only pill (24 days of drospironene 4 mg and 4 days of placebo) in 1,571 users. No BMI cutoff was used, but overall only 71 participants (4.6%) were obese. One study included desogestrel 0.075 mg (in a regimen of 28 active pills) as a comparator for safety. 

The overall Pearl Index for users 35 years or younger (1,251 users) was 1.0 (95% CI, 0.4-2.0). The "method failure Pearl Index" in users 35 years or younger, which included all pregnancies during "perfect medication cycles," was 1.3 (95% CI, 0.5-2.5). 

The most common adverse effects were acne (6.6% in study 1 and 4.4% in study 2), headache (4.5% in study 1), and irregular bleeding (4.4% in study 2). No cases of VTE occurred; there was 1 case of asymptomatic hyperkalemia. Additional laboratory values and vital signs showed no significant changes. The trend in bleeding was similar to that in the US studies, but it is interesting to note that there were significantly lower rates of unscheduled bleeding or spotting in drospirenone users than in desogestrel users (67.9% vs 86.5%, respectively; P<.001).

Continue to: Evidence supports 6 years' use of a levonorgestrel 52-mg IUS...

Westhoff CL, Keder LM, Gangestad A, et al. Six-year contraceptive efficacy and continued safety of a levonorgestrel 52-mg intrauterine system. Contraception. 2020;101:159-161. 

Two levonorgestrel 52-mg IUS products are on the market, both of which were approved for 5 years of use. The ACCESS IUS study (A Comprehensive Contraceptive Efficacy and Safety Study of an IUS) is an ongoing phase 3 trial to assess the safety and efficacy of a levonorgestrel 52-mg IUS (Liletta) for up to 10 years of use in US women. Westhoff and colleagues presented the data used for this IUS to gain approval for 6 years of use as of October 2019. The report included safety information for all users, with use exceeding 8 years in 122 participants. 

In year 6 of the ongoing trial, there were no on-treatment pregnancies with a 6-year life table pregnancy rate of 0.87 (95% CI, 0.44-1.70). Forty percent of users reported amenorrhea in the 90 days preceding the end of year 6, consistent with prior data after 3 years of use (FIGURE 3). The most common adverse effects over 6 or more years of use were bacterial vulvovaginal infections and urinary tract infections. 

Long-term IUS effectiveness 

Overall, in users aged 16 to 35 years, 72% discontinued study participation, most frequently due to an adverse event (19.2%) or to seeking pregnancy (15.5%). Through 6 or more years of use, overall discontinuation rates for expulsion (4.0%) and bleeding symptoms (2.3%) were very low, with 2 expulsions occurring in year 6 and only 1 participant discontinuing in year 6 for a bleeding symptom. These findings are consistent with those found at 5 years of IUS use and are representative of continued efficacy as well as overall low frequency of new significant events with extended use.¹¹

A vaginal ring that can be reused for up to 1 year and a progestin-only pill (POP) with a wider window for missed pills are 2 of the novel contraceptive products introduced to the market this year. In addition, an ongoing study of the levonorgestrel 52-mg intrauterine system (IUS) continues to provide evidence on its extended duration of use, now approved through 6 years.

The segesterone acetate (SA) and ethinyl estradiol (EE) vaginal ring (Annovera) is new among contraceptive options. Segesterone acetate is a novel progestin that can be used only via nonoral routes; it binds specifically to progesterone receptors without estrogenic or antiandrogen effects.¹ Unlike the etonogestrel and ethinyl estradiol ring (NuvaRing; for which generic products became available this past year), which is used for 1 cycle and then thrown away, the SA/EE ring is effective for 13 consecutive cycles. It does not require refrigeration when not in use.² Because a single ring can be used for 13 cycles, users in locations without laws that mandate a 12-month supply of pills, patches, and rings need less frequent visits to the pharmacy or clinic.

Progestin-only contraceptive pills are an important option for patients who desire hormonal contraception and have contraindications to estrogen, such as migraines with aura, cardiovascular risk factors, and being in the early postpartum period.³ In the United States, current POPs contain norethindrone, which has a 3-hour window for missed pills⁴; a desogestrel-only pill available outside the United States has a 12-hour window.⁵ Both are provided as a 28-day pill pack for continuous use, and both result in undesirable bleeding patterns in some users.

The prolonged half-life of drospirenone, another progestin, gives it the potential to increase reliability in the setting of missed or delayed pills and improve bleeding patterns. A new POP contraceptive contains drospirenone (Slynd) and is available in a 28-day pack with a 24-day supply of hormone and a 4-day supply of placebo; it provides a window for missed pill use similar to that for combined hormonal contraception (CHC) as well as a placebo period for a timed withdrawal bleed.^6,7

Liletta is a well-known levonorgestrel 52-mg IUS that was first approved by the US Food and Drug Administration (FDA) in 2015. An ongoing clinical trial has been the basis for approval of this IUS for use in increasing durations, from 3 years initially to 4 and then 5 years. The newest data indicate efficacy up to 6 years.⁸

Continue to: Combined hormonal vaginal system provides a year's contraception with an acceptable safety profile...

Combined hormonal vaginal system provides a year's contraception with an acceptable safety profile 

Archer DF, Merkatz RB, Bahamondes L, et al. Efficacy of the 1-year (13-cycle) segesterone acetate and ethinylestradiol contraceptive vaginal system: results of two multicentre, open-label, single-arm, phase 3 trials. Lancet Glob Health. 2019;7:e1054-e1064. 

Gemzell-Danielsson K, Sitruk-Ware R, Creinin MD, et al. Segesterone acetate/ethinyl estradiol 12-month contraceptive vaginal system safety evaluation. Contraception. 2019;99:323-328. 

Archer and colleagues reported the results of 2 pivotal multicenter, open-label, phase 3 trials, which included 2,265 users, conducted to evaluate efficacy and return to menses or pregnancy after use of the 1-year (13 cycles) SA/EE contraceptive vaginal system (CVS). 

Details of the efficacy study 

The study included 1,130 women in a US-only study and 1,135 women in an international study with sites in the United States, Australia, Brazil, Chile, Dominican Republic, Finland, Hungary, and Sweden. Participants used the CVS for 21 days followed by a 7-day use-free interval for up to 13 consecutive cycles; they were instructed not to remove the CVS for more than 2 hours during the 21 days of use. 

Primary and secondary efficacy outcomes were calculated using the Pearl Index and an intention-to-treat Kaplan-Meier life table, respectively. At the end of the study, users who desired not to continue hormonal contraception or to become pregnant were followed up for 6 months to evaluate return to menses or pregnancy. 

Year-long effectiveness 

The investigators reported an overall Pearl index of 2.98 (95% confidence interval [CI], 2.13-4.06) and a Kaplan-Meier life table cumulative efficacy rate of 97.5% (FIGURE 1), consistent with other recently approved CHC methods. Women from non-European sites, who primarily were US participants, had a Pearl Index of 3.25 (95% CI, 2.35-4.37), and participants from the European sites had a Pearl Index of 0.47 (95% CI, 0.03-2.07). Importantly, CVS removal had a significant impact on efficacy, with a Pearl Index of 5.98 (95% CI, 2.46-9.27) in users reporting CVS removals for longer than 2 hours, suggesting escape ovulation with improper use. The Pearl Index was highest in users aged 18 to 19 years and was not affected by body mass index (BMI), although 91% of users had a BMI of 29.0 kg/m² or lower. 

There was no trend for a change in pregnancy risk across 13 cycles, providing evidence of CVS efficacy throughout a full year's use. The follow-up portion of the study included 290 users who were not continuing hormonal contraception at study end; all follow-up participants reported return to menses after method discontinuation. 

Clinical safety data 

To evaluate safety outcomes from clinical studies on the CVS containing SA/EE, Gemzell-Danielsson and colleagues analyzed 9 studies. Most of the data were derived from 2 phase 3, multicenter trials (as discussed above), with supporting evidence from 7 other studies. 

Adverse events reported 

Among 2,308 CVS users in the phase 3 trials, 87% reported at least 1 adverse effect, with most of mild or moderate severity. These included headache, 26%; nausea, 18%; vaginal discharge, 10%; and metrorrhagia, 7%. Overall, 12% of CVS users discontinued use due to an adverse effect. Two percent of users experienced severe adverse effects, including venous thromboembolism (VTE), allergic reaction, gallbladder disease, and spontaneous abortion. 

In the US-only phase 3 trial, 2 VTE events occurred in the first 6 months in women with baseline BMI greater than 29.0 kg/m²; therefore, enrollment of patients with a BMI greater than 29.0 kg/m² was halted and current users meeting that criteria were discontinued. Notably, no cases of VTE occurred in studies with a segesterone acetate-only CVS; this suggests that risk can be attributed to the estrogen component. Overall, 4 nonfatal VTEs occurred, all among the 1,536 women enrolled in the phase 3 trials (4 of 1,536 [0.3%]); at least 3 of these cases occurred in users with VTE risk factors (TABLE 1). The estimated VTE rate in CVS users with a BMI greater than 29.0 kg/m2 is 10.8/10,000 women-years (95% CI, 8.9-13.1). 

Complete expulsion of the CVS occurred in 7% of cycles and partial expulsion in 19.5% of cycles; users reported expulsion more frequently in the first cycle, most (about 70%) of which were partial expulsions. Of the laboratory values and vital signs studied, including weight, users had no clinically relevant changes from baseline.

Continue to: New drospirenone pill is an effective POP option...

New drospirenone pill is an effective POP option 

Kimble T, Burke AE, Barnhart KT, et al. A 1-year prospective, open-label, single-arm, multicenter, phase 3 trial of the contraceptive efficacy and safety of the oral progestin-only pill drospirenone 4 mg using a 24/4-day regimen. Contracept X. 2020;2:100020. 

Palacios S, Colli E, Regidor PA. Multicenter, phase III trials on the contraceptive efficacy, tolerability and safety of a new drospirenone-only pill. Acta Obstet Gynecol Scand. 2019;98:1549-1557. 

In a prospective, single-arm, multicenter phase 3 trial in the United States, Kimble and colleagues evaluated the efficacy and safety of an oral drospirenone POP in a cyclic 24-day hormone/4-day placebo regimen. The trial included 1,006 users. No BMI cutoff was used, and about one-third of study participants were obese (BMI >30.0 kg/m²). Women were instructed to take a missed tablet as soon as remembered if within 24 hours or with the next scheduled dose if more than 24 hours late. 

Contraceptive effectiveness 

The Pearl Index for nonbreastfeeding users aged 35 years or younger with pregnancies confirmed by a quantitative serum ß-human chorionic gonadotropin test (915 users) was 2.9 (95% CI, 1.5-5.1). Of note, 2 out of 15 on-treatment pregnancies were excluded from this calculation because of protocol site violations, as were 3 pregnancies that were unconfirmed. In the modified full analysis set of 915 users, 36% were obese (BMI≥30 kg/m²), and the Pearl Index was noted to be unaffected by BMI (TABLE 2). 

While 61% of women reported adverse effects, more than 95% of these were mild or moderate in intensity, including headache, nausea, dysmenorrhea, metrorrhagia, and breast pain. No VTE occurred. The frequency of hyperkalemia was 0.5%, and there was no evidence of hypotension, which is significant due to the antimineralocorticoid activity of drospirenone. All cases of hyperkalemia were considered mild, and all women were asymptomatic. There were no clinically relevant changes in body weight, gynecologic exam, or other laboratory values. 

With increased cycles of use, the number of days with bleeding or spotting generally decreased and amenorrhea increased. However, in cycles 11 to 13, 41.6% of users still had unscheduled bleeding (reduced from 57.0% at cycles 2-4), and 29.0% had scheduled bleeding (decreased from 44% at cycles 2-4) (FIGURE 2). With these bleeding patterns, 86.2% of users agreed or strongly agreed that they were satisfied with the product. 

European multicenter study of drospironene 

In a European investigation, Palacios and colleagues pooled and analyzed data from 2 phase 3 multicenter trials to assess the efficacy, tolerability, and safety of the same drospirenone-only pill (24 days of drospironene 4 mg and 4 days of placebo) in 1,571 users. No BMI cutoff was used, but overall only 71 participants (4.6%) were obese. One study included desogestrel 0.075 mg (in a regimen of 28 active pills) as a comparator for safety. 

The overall Pearl Index for users 35 years or younger (1,251 users) was 1.0 (95% CI, 0.4-2.0). The "method failure Pearl Index" in users 35 years or younger, which included all pregnancies during "perfect medication cycles," was 1.3 (95% CI, 0.5-2.5). 

The most common adverse effects were acne (6.6% in study 1 and 4.4% in study 2), headache (4.5% in study 1), and irregular bleeding (4.4% in study 2). No cases of VTE occurred; there was 1 case of asymptomatic hyperkalemia. Additional laboratory values and vital signs showed no significant changes. The trend in bleeding was similar to that in the US studies, but it is interesting to note that there were significantly lower rates of unscheduled bleeding or spotting in drospirenone users than in desogestrel users (67.9% vs 86.5%, respectively; P<.001).

Continue to: Evidence supports 6 years' use of a levonorgestrel 52-mg IUS...

Westhoff CL, Keder LM, Gangestad A, et al. Six-year contraceptive efficacy and continued safety of a levonorgestrel 52-mg intrauterine system. Contraception. 2020;101:159-161. 

Two levonorgestrel 52-mg IUS products are on the market, both of which were approved for 5 years of use. The ACCESS IUS study (A Comprehensive Contraceptive Efficacy and Safety Study of an IUS) is an ongoing phase 3 trial to assess the safety and efficacy of a levonorgestrel 52-mg IUS (Liletta) for up to 10 years of use in US women. Westhoff and colleagues presented the data used for this IUS to gain approval for 6 years of use as of October 2019. The report included safety information for all users, with use exceeding 8 years in 122 participants. 

In year 6 of the ongoing trial, there were no on-treatment pregnancies with a 6-year life table pregnancy rate of 0.87 (95% CI, 0.44-1.70). Forty percent of users reported amenorrhea in the 90 days preceding the end of year 6, consistent with prior data after 3 years of use (FIGURE 3). The most common adverse effects over 6 or more years of use were bacterial vulvovaginal infections and urinary tract infections. 

Long-term IUS effectiveness 

Overall, in users aged 16 to 35 years, 72% discontinued study participation, most frequently due to an adverse event (19.2%) or to seeking pregnancy (15.5%). Through 6 or more years of use, overall discontinuation rates for expulsion (4.0%) and bleeding symptoms (2.3%) were very low, with 2 expulsions occurring in year 6 and only 1 participant discontinuing in year 6 for a bleeding symptom. These findings are consistent with those found at 5 years of IUS use and are representative of continued efficacy as well as overall low frequency of new significant events with extended use.¹¹

A vaginal ring that can be reused for up to 1 year and a progestin-only pill (POP) with a wider window for missed pills are 2 of the novel contraceptive products introduced to the market this year. In addition, an ongoing study of the levonorgestrel 52-mg intrauterine system (IUS) continues to provide evidence on its extended duration of use, now approved through 6 years.

The segesterone acetate (SA) and ethinyl estradiol (EE) vaginal ring (Annovera) is new among contraceptive options. Segesterone acetate is a novel progestin that can be used only via nonoral routes; it binds specifically to progesterone receptors without estrogenic or antiandrogen effects.¹ Unlike the etonogestrel and ethinyl estradiol ring (NuvaRing; for which generic products became available this past year), which is used for 1 cycle and then thrown away, the SA/EE ring is effective for 13 consecutive cycles. It does not require refrigeration when not in use.² Because a single ring can be used for 13 cycles, users in locations without laws that mandate a 12-month supply of pills, patches, and rings need less frequent visits to the pharmacy or clinic.

Progestin-only contraceptive pills are an important option for patients who desire hormonal contraception and have contraindications to estrogen, such as migraines with aura, cardiovascular risk factors, and being in the early postpartum period.³ In the United States, current POPs contain norethindrone, which has a 3-hour window for missed pills⁴; a desogestrel-only pill available outside the United States has a 12-hour window.⁵ Both are provided as a 28-day pill pack for continuous use, and both result in undesirable bleeding patterns in some users.

The prolonged half-life of drospirenone, another progestin, gives it the potential to increase reliability in the setting of missed or delayed pills and improve bleeding patterns. A new POP contraceptive contains drospirenone (Slynd) and is available in a 28-day pack with a 24-day supply of hormone and a 4-day supply of placebo; it provides a window for missed pill use similar to that for combined hormonal contraception (CHC) as well as a placebo period for a timed withdrawal bleed.^6,7

Liletta is a well-known levonorgestrel 52-mg IUS that was first approved by the US Food and Drug Administration (FDA) in 2015. An ongoing clinical trial has been the basis for approval of this IUS for use in increasing durations, from 3 years initially to 4 and then 5 years. The newest data indicate efficacy up to 6 years.⁸

Continue to: Combined hormonal vaginal system provides a year's contraception with an acceptable safety profile...

Combined hormonal vaginal system provides a year's contraception with an acceptable safety profile 

Archer DF, Merkatz RB, Bahamondes L, et al. Efficacy of the 1-year (13-cycle) segesterone acetate and ethinylestradiol contraceptive vaginal system: results of two multicentre, open-label, single-arm, phase 3 trials. Lancet Glob Health. 2019;7:e1054-e1064. 

Gemzell-Danielsson K, Sitruk-Ware R, Creinin MD, et al. Segesterone acetate/ethinyl estradiol 12-month contraceptive vaginal system safety evaluation. Contraception. 2019;99:323-328. 

Archer and colleagues reported the results of 2 pivotal multicenter, open-label, phase 3 trials, which included 2,265 users, conducted to evaluate efficacy and return to menses or pregnancy after use of the 1-year (13 cycles) SA/EE contraceptive vaginal system (CVS). 

Details of the efficacy study 

The study included 1,130 women in a US-only study and 1,135 women in an international study with sites in the United States, Australia, Brazil, Chile, Dominican Republic, Finland, Hungary, and Sweden. Participants used the CVS for 21 days followed by a 7-day use-free interval for up to 13 consecutive cycles; they were instructed not to remove the CVS for more than 2 hours during the 21 days of use. 

Primary and secondary efficacy outcomes were calculated using the Pearl Index and an intention-to-treat Kaplan-Meier life table, respectively. At the end of the study, users who desired not to continue hormonal contraception or to become pregnant were followed up for 6 months to evaluate return to menses or pregnancy. 

Year-long effectiveness 

The investigators reported an overall Pearl index of 2.98 (95% confidence interval [CI], 2.13-4.06) and a Kaplan-Meier life table cumulative efficacy rate of 97.5% (FIGURE 1), consistent with other recently approved CHC methods. Women from non-European sites, who primarily were US participants, had a Pearl Index of 3.25 (95% CI, 2.35-4.37), and participants from the European sites had a Pearl Index of 0.47 (95% CI, 0.03-2.07). Importantly, CVS removal had a significant impact on efficacy, with a Pearl Index of 5.98 (95% CI, 2.46-9.27) in users reporting CVS removals for longer than 2 hours, suggesting escape ovulation with improper use. The Pearl Index was highest in users aged 18 to 19 years and was not affected by body mass index (BMI), although 91% of users had a BMI of 29.0 kg/m² or lower. 

There was no trend for a change in pregnancy risk across 13 cycles, providing evidence of CVS efficacy throughout a full year's use. The follow-up portion of the study included 290 users who were not continuing hormonal contraception at study end; all follow-up participants reported return to menses after method discontinuation. 

Clinical safety data 

To evaluate safety outcomes from clinical studies on the CVS containing SA/EE, Gemzell-Danielsson and colleagues analyzed 9 studies. Most of the data were derived from 2 phase 3, multicenter trials (as discussed above), with supporting evidence from 7 other studies. 

Adverse events reported 

Among 2,308 CVS users in the phase 3 trials, 87% reported at least 1 adverse effect, with most of mild or moderate severity. These included headache, 26%; nausea, 18%; vaginal discharge, 10%; and metrorrhagia, 7%. Overall, 12% of CVS users discontinued use due to an adverse effect. Two percent of users experienced severe adverse effects, including venous thromboembolism (VTE), allergic reaction, gallbladder disease, and spontaneous abortion. 

In the US-only phase 3 trial, 2 VTE events occurred in the first 6 months in women with baseline BMI greater than 29.0 kg/m²; therefore, enrollment of patients with a BMI greater than 29.0 kg/m² was halted and current users meeting that criteria were discontinued. Notably, no cases of VTE occurred in studies with a segesterone acetate-only CVS; this suggests that risk can be attributed to the estrogen component. Overall, 4 nonfatal VTEs occurred, all among the 1,536 women enrolled in the phase 3 trials (4 of 1,536 [0.3%]); at least 3 of these cases occurred in users with VTE risk factors (TABLE 1). The estimated VTE rate in CVS users with a BMI greater than 29.0 kg/m2 is 10.8/10,000 women-years (95% CI, 8.9-13.1). 

Complete expulsion of the CVS occurred in 7% of cycles and partial expulsion in 19.5% of cycles; users reported expulsion more frequently in the first cycle, most (about 70%) of which were partial expulsions. Of the laboratory values and vital signs studied, including weight, users had no clinically relevant changes from baseline.

Continue to: New drospirenone pill is an effective POP option...

New drospirenone pill is an effective POP option 

Kimble T, Burke AE, Barnhart KT, et al. A 1-year prospective, open-label, single-arm, multicenter, phase 3 trial of the contraceptive efficacy and safety of the oral progestin-only pill drospirenone 4 mg using a 24/4-day regimen. Contracept X. 2020;2:100020. 

Palacios S, Colli E, Regidor PA. Multicenter, phase III trials on the contraceptive efficacy, tolerability and safety of a new drospirenone-only pill. Acta Obstet Gynecol Scand. 2019;98:1549-1557. 

In a prospective, single-arm, multicenter phase 3 trial in the United States, Kimble and colleagues evaluated the efficacy and safety of an oral drospirenone POP in a cyclic 24-day hormone/4-day placebo regimen. The trial included 1,006 users. No BMI cutoff was used, and about one-third of study participants were obese (BMI >30.0 kg/m²). Women were instructed to take a missed tablet as soon as remembered if within 24 hours or with the next scheduled dose if more than 24 hours late. 

Contraceptive effectiveness 

The Pearl Index for nonbreastfeeding users aged 35 years or younger with pregnancies confirmed by a quantitative serum ß-human chorionic gonadotropin test (915 users) was 2.9 (95% CI, 1.5-5.1). Of note, 2 out of 15 on-treatment pregnancies were excluded from this calculation because of protocol site violations, as were 3 pregnancies that were unconfirmed. In the modified full analysis set of 915 users, 36% were obese (BMI≥30 kg/m²), and the Pearl Index was noted to be unaffected by BMI (TABLE 2). 

While 61% of women reported adverse effects, more than 95% of these were mild or moderate in intensity, including headache, nausea, dysmenorrhea, metrorrhagia, and breast pain. No VTE occurred. The frequency of hyperkalemia was 0.5%, and there was no evidence of hypotension, which is significant due to the antimineralocorticoid activity of drospirenone. All cases of hyperkalemia were considered mild, and all women were asymptomatic. There were no clinically relevant changes in body weight, gynecologic exam, or other laboratory values. 

With increased cycles of use, the number of days with bleeding or spotting generally decreased and amenorrhea increased. However, in cycles 11 to 13, 41.6% of users still had unscheduled bleeding (reduced from 57.0% at cycles 2-4), and 29.0% had scheduled bleeding (decreased from 44% at cycles 2-4) (FIGURE 2). With these bleeding patterns, 86.2% of users agreed or strongly agreed that they were satisfied with the product. 

European multicenter study of drospironene 

In a European investigation, Palacios and colleagues pooled and analyzed data from 2 phase 3 multicenter trials to assess the efficacy, tolerability, and safety of the same drospirenone-only pill (24 days of drospironene 4 mg and 4 days of placebo) in 1,571 users. No BMI cutoff was used, but overall only 71 participants (4.6%) were obese. One study included desogestrel 0.075 mg (in a regimen of 28 active pills) as a comparator for safety. 

The overall Pearl Index for users 35 years or younger (1,251 users) was 1.0 (95% CI, 0.4-2.0). The "method failure Pearl Index" in users 35 years or younger, which included all pregnancies during "perfect medication cycles," was 1.3 (95% CI, 0.5-2.5). 

The most common adverse effects were acne (6.6% in study 1 and 4.4% in study 2), headache (4.5% in study 1), and irregular bleeding (4.4% in study 2). No cases of VTE occurred; there was 1 case of asymptomatic hyperkalemia. Additional laboratory values and vital signs showed no significant changes. The trend in bleeding was similar to that in the US studies, but it is interesting to note that there were significantly lower rates of unscheduled bleeding or spotting in drospirenone users than in desogestrel users (67.9% vs 86.5%, respectively; P<.001).

Continue to: Evidence supports 6 years' use of a levonorgestrel 52-mg IUS...

Westhoff CL, Keder LM, Gangestad A, et al. Six-year contraceptive efficacy and continued safety of a levonorgestrel 52-mg intrauterine system. Contraception. 2020;101:159-161. 

Two levonorgestrel 52-mg IUS products are on the market, both of which were approved for 5 years of use. The ACCESS IUS study (A Comprehensive Contraceptive Efficacy and Safety Study of an IUS) is an ongoing phase 3 trial to assess the safety and efficacy of a levonorgestrel 52-mg IUS (Liletta) for up to 10 years of use in US women. Westhoff and colleagues presented the data used for this IUS to gain approval for 6 years of use as of October 2019. The report included safety information for all users, with use exceeding 8 years in 122 participants. 

In year 6 of the ongoing trial, there were no on-treatment pregnancies with a 6-year life table pregnancy rate of 0.87 (95% CI, 0.44-1.70). Forty percent of users reported amenorrhea in the 90 days preceding the end of year 6, consistent with prior data after 3 years of use (FIGURE 3). The most common adverse effects over 6 or more years of use were bacterial vulvovaginal infections and urinary tract infections. 

Long-term IUS effectiveness 

Overall, in users aged 16 to 35 years, 72% discontinued study participation, most frequently due to an adverse event (19.2%) or to seeking pregnancy (15.5%). Through 6 or more years of use, overall discontinuation rates for expulsion (4.0%) and bleeding symptoms (2.3%) were very low, with 2 expulsions occurring in year 6 and only 1 participant discontinuing in year 6 for a bleeding symptom. These findings are consistent with those found at 5 years of IUS use and are representative of continued efficacy as well as overall low frequency of new significant events with extended use.¹¹

Psoriasis is a common chronic, multisystem, inflammatory disease with predominantly skin and joint manifestations that affects approximately 2% of the world’s population.¹ It occurs in a variety of clinical forms, from a few well-demarcated, erythematous plaques with a silvery scale to involvement of almost the entire body surface area. Beyond the debilitating physical ailments of the disease, psoriasis also may have psychosocial effects on quality of life.² The pathogenesis of psoriasis is not fully understood but represents a complex multifactorial disease with both immune-mediated and genetic components. Characterized by hyperplasia of epidermal keratinocytes, psoriasis is shown to be mediated by infiltration of T-cell lymphocytes with an increase of various inflammatory cytokines, including tumor necrosis factor (TNF) α.³ More recently, interactions of helper T cells (T_H17) via IL-17 and IL-23 have been supported to play a major role in the pathogenesis of psoriasis.^4,5

With the growing understanding of the pathophysiology of psoriasis, focused biologics have been developed to target specific cytokines implicated in the disease process and have been increasingly utilized. Tumor necrosis factor α inhibitors, including adalimumab, infliximab, and etanercept, along with the IL-12/IL-23 inhibitor ustekinumab, have been revolutionary in psoriasis treatment by providing safe and effective long-term therapy; however, there is concern of life-threatening infections with biologics because of the immunosuppressive effects and mechanisms of action.⁶ Specifically, there have been reported cases of deep fungal infections associated with TNF-α inhibitor use.⁷

Recently, the advent of IL-17 and IL-23 inhibitors has garnered notable interest in these biologics as promising treatments for psoriasis. With IL-17 and IL-23 supported to have a major role in the pathogenesis of psoriasis, targeting the cytokine is not only logical but also has proven to be effacacious.^8-10 Secukinumab, ixekizumab, and brodalumab are IL-17 inhibitors that have been approved by the US Food and Drug Administration (FDA) for the treatment of psoriasis. Secukinumab and ixekizumab are anti–IL-17A monoclonal antibodies, whereas brodalumab is an anti–IL-17 receptor antibody. Risankizumab, guselkumab, and tildrakizumab are IL-23 inhibitors that also have been approved by the FDA for the treatment of psoriasis. As with older biologics, there is concern over the safety of these inhibitors because of the central role of IL-17 and IL-23 in both innate and adaptive immune responses, particularly against fungi.¹¹ Therefore, use of biologics targeting IL-17 and IL-23 may increase susceptibility to deep fungal infections.

Safety data and discussion of the risk for deep fungal infections from IL-17, IL-12/IL-23, and IL-23 inhibitor use for psoriasis treatment currently are lacking. Given the knowledge gap, we sought to synthesize and review the current evidence on risks for deep fungal infections during biologic therapy in patients with psoriasis, with a focus on IL-17 inhibitor therapies.

METHODS

A PubMed search of articles indexed for MEDLINE from database inception to 2019 (1946-2019) was performed to find randomized controlled trials (RCTs), including extended trials and clinical trials, for IL-17, IL-12/IL-23, and IL-23 inhibitors approved by the FDA for psoriasis treatment. The following keywords were used: psoriasis or inflammatory disease and secukinumab, ixekizumab, brodalumab, ustekinumab, risankizumab, guselkumab, or tildrakizumab. Studies were restricted to the English-language literature, and those that did not provide adequate safety data on the specific types of infections that occurred were excluded.

RESULTSIL-17 Inhibitors

Our search yielded RCTs, some including extension trials, and clinical trials of IL-17 inhibitors used for psoriatic disease and other nonpsoriatic conditions (Table).

Risk for Deep Fungal Infection With Secukinumab
The queried studies included 20 RCTs or clinical trials along with extension trials of 3746 patients with psoriasis or other inflammatory conditions, with follow-up ranging from 12 to 52 weeks. In a 3-year extension study of SCULPTURE, Bissonnette et al¹² reported no new safety concerns for the 340 patients with moderate to severe psoriasis treated with secukinumab. Common adverse events (AEs) included nasopharyngitis, upper respiratory tract infections, and headache, but there were no reports of deep fungal infections.¹² In a subsequent 5-year analysis of 168 patients that focused on the 300-mg fixed interval treatment with secukinumab, the safety profile remained favorable, with 0 reports of invasive fungal infections.¹³ A study (FEATURE) of 118 patients with psoriasis treated with a prefilled syringe of 300 or 150 mg of secukinumab also described an acceptable safety profile and reported no deep fungal infections.¹⁴ JUNCTURE, another study utilizing autoinjectors, also found that treatment with 300 or 150 mg of secukinumab was well tolerated in 121 patients, with no deep fungal infections.¹⁵ Common AEs for both studies included nasopharyngitis and headache.^14,15 A 24-week phase 3 study for scalp psoriasis treated with secukinumab also reported 0 deep fungal infections in 51 patients.¹⁶ In an RCT comparing secukinumab and ustekinumab for moderate to severe plaque psoriasis, Blauvelt et al¹⁷ demonstrated that the incidence of serious AEs was comparable between the 2 groups, with no reports of invasive fungal infections in the 334 patients exposed to secukinumab. The CLEAR study, which compared secukinumab and ustekinumab, also found no reported deep fungal disease in the 335 patients exposed to secukinumab.¹⁸ Secukinumab exhibited a similar safety profile to ustekinumab in both studies, with common AEs being headache and nasopharyngitis.^17,18 The GESTURE study investigated the efficacy of secukinumab in 137 patients with palmoplantar psoriasis and reported a favorable profile with no reports of deep fungal disease.¹⁹ In a subanalysis of the phase 3 study ERASURE, secukinumab was shown to have a robust and sustainable efficacy in 58 Japanese patients with moderate to severe plaque psoriasis, and there were no reports of invasive fungal infections.²⁰ Another subanalysis of 36 Taiwanese patients from the ERASURE study also had similar findings, with no dose relationship observed for AEs.²¹ In a phase 2 study of 103 patients with psoriasis, Papp et al²² demonstrated AE rates that were similar across different doses of secukinumab—3×150 mg, 3×75 mg, 3×25 mg, and 1×25 mg—and described no incidences of invasive fungal disease. In a phase 2 regimen-finding study of 337 patients conducted by Rich et al,²³ the most commonly reported AEs included nasopharyngitis, worsening psoriasis, and upper respiratory tract infections, but there were no reported deep fungal infections.

Our search also resulted in studies specific to the treatment of psoriatic arthritis (PsA) with secukinumab. McInnes et al⁹ conducted a phase 2 proof-of-concept trial for patients with PsA and reported no deep fungal infections in 28 patients exposed to 10 mg/kg of secukinumab. A 2-year follow-up with the cohort from FUTURE 1, a phase 3 clinical trial, also showed no new or unexpected safety signals in 404 patients exposed to 150 or 75 mg of secukinumab, including no reports of invasive fungal disease.²⁴ FUTURE 2, a phase 3 clinical trial, demonstrated that the most common AE was upper respiratory tract infection in the 299 patients treatedwith secukinumab, but there were no recorded invasive fungal infections.²⁵ In FUTURE 3, 277 patients were treated with secukinumab, with 14 nonserious candida infections but no observed deep fungal infections.²⁶ A study comparing secukinumab to fumaric acid esters reported that 6 of 105 patients treated with secukinumab also experienced superficial candidiasis, but there were no reports of deep fungal disease.²⁷

Secukinumab also has been used in the treatment of ankylosing spondylitis in a phase 3 RCT (MEASURE 1) in which 4 cases of superficial candidiasis were reported (0.7 cases per 100 patient-years of secukinumab) that were all resolved with standard antifungal therapy.²⁸ In MEASURE 2, a 5-year phase 3 RCT, 145 patients were treated with secukinumab for ankylosing spondylitis, with common AEs including nasopharyngitis, diarrhea, and upper respiratory tract infection, but there were no reports of any invasive fungal infections.²⁹ MEASURE 3 also demonstrated similar results in which no invasive fungal infections were observed.³⁰

Risk for Deep Fungal Infection With Ixekizumab
The queried studies included 7 RCTs or clinical trials of 3523 patients with psoriasis or other inflammatory conditions, with follow-up ranging from 12 to 52 weeks. In UNCOVER-A, a phase 3 RCT of the pharmacokinetics and safety of ixekizumab, 204 patients were randomized to a prefilled syringe or autoinjector; 48% of patients experienced AEs, but no invasive fungal infections were observed.³¹ In an analysis of 3 phase 3 trials of ixekizumab including a total 2334 patients treated with ixekizumab from UNCOVER-1, UNCOVER-2, and UNCOVER-3, oral candidiasis frequently was reported, but no candidal infections met criteria for serious invasive infection.³² In UNCOVER-J, a 52-week phase 3 open-label trial of Japanese patients, 91 patients were treated for plaque psoriasis, erythrodermic psoriasis, or generalized pustular psoriasis using ixekizumab; the most common AEs included allergic reactions and injection-site reactions. One case of oral candidiasis was reported, but there were no reported cases of invasive fungal infections.³³ A comparison of ixekizumab vs ustekinumab from the IXORA-S trial demonstrated no substantial differences in AEs between the two, and no cases of deep fungal infections were reported. The most common AE between the 2 groups was nasopharyngitis.³⁴ An open-label extension over 4 years of a phase 2 RCT treated 211 patients with either 120 or 80 mg of ixekizumab; 87% of patients had experienced at least 1 AE, and all AEs were considered mild or moderate in severity, with no invasive fungal disease.³⁵

Our search also resulted in 1 study specific to the treatment of PsA with ixekizumab. A phase 3, 52-week study of patients treated with ixekizumab for PsA observed 2 incidences of oral candidiasis and nail candida infections, but no invasive fungal infections were reported.³⁶

We also found 1 study of ixekizumab used in the treatment of ankylosing spondylitis. COAST-V was a phase 3 RCT of patients treated for ankylosing spondylitis in which 164 patients were treated with ixekizumab; no serious AEs were recorded, including 0 deep fungal infections. The most common AEs observed were nasopharyngitis and upper respiratory tract infections.³⁷

Risk for Deep Fungal Infection With Brodalumab
The queried studies included 9 RCTs and 3 clinical trials along with extension trials of 1599 patients with psoriasis or other inflammatory conditions, with follow-up ranging from 12 to 120 weeks. In a phase 2 RCT of Japanese patients with moderate to severe plaque psoriasis, 113 patients were treated with 70, 140, or 210 mg of brodalumab, and the most common AEs were nasopharyngitis, diarrhea, and upper respiratory tract inflammation. There were no reported cases of fungal infections in the study.³⁸ In an open-label extension study of Japanese patients that evaluated the long-term clinical safety of brodalumab, 145 patients were enrolled and observed similar AEs to the RCT, with 7 patients experiencing oral candidiasis and 1 patient having skin candidiasis, but there were no observed deep fungal infections.³⁹ In AMG 827, which evaluated the efficacy and safety of brodalumab, 320 patients were treated, and only 2 serious AEs were reported, neither of which were deep fungal disease.¹⁰ A phase 3 RCT conducted by Papp et al⁴⁰ (AMAGINE-1) also treated 441 patients with moderate to severe plaque psoriasis with brodalumab and observed candida infections in 9 patients that were mild to moderate and responsive to treatment, with no patients discontinuing the study. In a 120-week open-label extension study of 181 patients, Papp et al⁴¹ reported 8% of patients experienced serious AEs, with 1 case of latent tuberculosis that led to withdrawal of treatment. A study also investigated the efficacy and safety of brodalumab in 30 patients with generalized pustular psoriasis or psoriatic erythroderma and observed 2 cases of mild candida infections that resolved with treatment. There were no reports of invasive fungal disease.⁴²

Our search also resulted in studies of brodalumab used in the treatment of PsA and nonpsoriatic diseases. In one phase 2 RCT, 113 patients with PsA were treated with 140 mg, 280 mg, or combined doses of brodalumab, with the most common AEs being nasopharyngitis, upper respiratory tract infection, and diarrhea, but there were no reports of deep fungal infection.⁴³ In a phase 1b trial of patients with methotrexate-resistant rheumatoid arthritis treated with brodalumab, common AEs reported included headache, cough, and abdominal pain, with only 1 case of oral candidiasis that was determined not to be drug related.⁴⁴ Finally, an RCT of patients with moderate to severe asthma treated 226 patients with brodalumab and reported a greater incidence of oral candidiasis in treatment groups compared with placebo (3.5% vs 0%) but saw no instances of invasive fungal infection.⁴⁵

IL-12/IL-23 Inhibitor

Risk for Deep Fungal Infection With Ustekinumab
The queried studies included 4 RCTs of 954 patients with psoriasis treated with ustekinumab (eTable).^46-49 Within these trials, there were no reported cases of serious infections involving deep fungal organisms during the stated follow-up period. The literature search also found long-term safety data from the ACCEPT and PHOENIX trials that included 5437 patients with psoriasis treated with ustekinumab.^66,67 There also were no demonstrated incidences of invasive fungal disease in these studies, with most cases of infection being common bacterial or viral infections.

IL-23 Inhibitors

Risk for Deep Fungal Infection With Risankizumab, Guselkumab, and Tildrakizumab
The queried studies included 16 RCTs or clinical trials for psoriatic patients treated with IL-23 inhibitors, including 5 with risankizumab,^50-54 9 with guselkumab,^55-63 and 2 with tildrakizumab.^64,65 Within these trials there were no observed cases of serious infections with deep fungal disease.

COMMENT

Our literature review has demonstrated that there does not appear to be an increased incidence of deep fungal infections for patients treated with IL-17, IL-12/IL-23, or IL-23 inhibitors for psoriatic disease. All of the reviewed studies found no cases of invasive fungal infections for patients with psoriasis treated with secukinumab, ixekizumab, brodalumab, ustekinumab, risankizumab, guselkumab, or tildrakizumab. Patients with other inflammatory conditions, such as ankylosing spondylitis, rheumatoid arthritis, and asthma, also did not appear to show an increased incidence of deep fungal disease.

Although these results show promising safety data for the use of these biologic therapies in treating inflammatory conditions, caution still is warranted, as these medications still are relatively new, with FDA approvals within the last 5 years. Safety data among different study populations also cannot be derived without further investigation, and much of the available literature is limited in long-term data. More extended trials or registry data from a large, broadly representative cohort are necessary to establish the long-term safety and risk for deep fungal infections with IL-17 and especially the newer IL-23 inhibitors.

A small percentage of patients from the reviewed literature did develop superficial candidiasis. This outcome can be expected, as the central role of IL-17 and IL-23 has been recognized in immunologic protection against infections, specifically against fungi.¹¹ Because all of the fungal infections reported for patients on IL-17 inhibitors were superficial candidiasis, guides for practical management and treatment should be implemented to standardize future research and care. A proposed screening algorithm for patients on these biologic therapies involves safety monitoring, including inspection of the oral cavity, folds, and genitals, along with inquiring about symptoms such as burning, dysgeusia, and dysuria.⁶⁸ If infection is suspected, confirmation by culture, molecular method, or optimally with esophagoscopy can be performed, and appropriate treatment may be initiated.⁶⁸ Patients with candida infections of the oral cavity, folds, or genitals can be placed on topical therapy such as nystatin, amphotericin B, ciclopirox, or other azoles, while those with infections of the esophagus can be started on oral fluconazole.⁶⁸

Although there were no reported cases of deep fungal infections, the theoretical risk for developing one while on IL-17 and IL-23 inhibitors may warrant further screening prior to beginning therapy. The TNF inhibitors approved for the treatment of psoriasis currently contain a black box warning for risk for disseminated and extrapulmonary histoplasmosis, coccidioidomycosis, blastomycosis, and other invasive fungal infections, which may highlight the importance of thorough evaluation and awareness of endemic areas for patients on biologics. Prior to initiating treatment with TNF inhibitors, current suggestions involve performing a thorough examination along with keeping a high index of suspicion for invasive fungal infections in patients who live in or have traveled to endemic regions.⁶⁹

Screening for invasive fungal infections for patients on TNF inhibitors involves questioning about potential exposures, such as demolition of old buildings, bird roosts, or spelunking.⁷⁰ Serologies or antigen testing can be used routinely, but as these tests are insensitive, empiric antifungal therapy should be initiated if there is high enough clinical suspicion.⁷¹ Currently, there are no clinical guidelines regarding fungal screening and initiation of IL-17 and IL-23 inhibitors for treatment of psoriasis and other inflammatory conditions, but careful stewardship over using these effective medications should still be practiced.

Upon review of the available safety data on the use of IL-17 and IL-23 inhibitors for the treatment of psoriasis and other inflammatory conditions, there does not appear to be an increased incidence of deep fungal infections. Physicians, however, should still be cautiously optimistic in prescribing these medications, as there is a theoretical risk for infection for all patients on biologics. A high index of suspicion for patients presenting with symptoms of fungal infections should be maintained, and appropriate diagnosis and management should be initiated if they do occur.

Psoriasis is a common chronic, multisystem, inflammatory disease with predominantly skin and joint manifestations that affects approximately 2% of the world’s population.¹ It occurs in a variety of clinical forms, from a few well-demarcated, erythematous plaques with a silvery scale to involvement of almost the entire body surface area. Beyond the debilitating physical ailments of the disease, psoriasis also may have psychosocial effects on quality of life.² The pathogenesis of psoriasis is not fully understood but represents a complex multifactorial disease with both immune-mediated and genetic components. Characterized by hyperplasia of epidermal keratinocytes, psoriasis is shown to be mediated by infiltration of T-cell lymphocytes with an increase of various inflammatory cytokines, including tumor necrosis factor (TNF) α.³ More recently, interactions of helper T cells (T_H17) via IL-17 and IL-23 have been supported to play a major role in the pathogenesis of psoriasis.^4,5

With the growing understanding of the pathophysiology of psoriasis, focused biologics have been developed to target specific cytokines implicated in the disease process and have been increasingly utilized. Tumor necrosis factor α inhibitors, including adalimumab, infliximab, and etanercept, along with the IL-12/IL-23 inhibitor ustekinumab, have been revolutionary in psoriasis treatment by providing safe and effective long-term therapy; however, there is concern of life-threatening infections with biologics because of the immunosuppressive effects and mechanisms of action.⁶ Specifically, there have been reported cases of deep fungal infections associated with TNF-α inhibitor use.⁷

Recently, the advent of IL-17 and IL-23 inhibitors has garnered notable interest in these biologics as promising treatments for psoriasis. With IL-17 and IL-23 supported to have a major role in the pathogenesis of psoriasis, targeting the cytokine is not only logical but also has proven to be effacacious.^8-10 Secukinumab, ixekizumab, and brodalumab are IL-17 inhibitors that have been approved by the US Food and Drug Administration (FDA) for the treatment of psoriasis. Secukinumab and ixekizumab are anti–IL-17A monoclonal antibodies, whereas brodalumab is an anti–IL-17 receptor antibody. Risankizumab, guselkumab, and tildrakizumab are IL-23 inhibitors that also have been approved by the FDA for the treatment of psoriasis. As with older biologics, there is concern over the safety of these inhibitors because of the central role of IL-17 and IL-23 in both innate and adaptive immune responses, particularly against fungi.¹¹ Therefore, use of biologics targeting IL-17 and IL-23 may increase susceptibility to deep fungal infections.

Safety data and discussion of the risk for deep fungal infections from IL-17, IL-12/IL-23, and IL-23 inhibitor use for psoriasis treatment currently are lacking. Given the knowledge gap, we sought to synthesize and review the current evidence on risks for deep fungal infections during biologic therapy in patients with psoriasis, with a focus on IL-17 inhibitor therapies.

METHODS

A PubMed search of articles indexed for MEDLINE from database inception to 2019 (1946-2019) was performed to find randomized controlled trials (RCTs), including extended trials and clinical trials, for IL-17, IL-12/IL-23, and IL-23 inhibitors approved by the FDA for psoriasis treatment. The following keywords were used: psoriasis or inflammatory disease and secukinumab, ixekizumab, brodalumab, ustekinumab, risankizumab, guselkumab, or tildrakizumab. Studies were restricted to the English-language literature, and those that did not provide adequate safety data on the specific types of infections that occurred were excluded.

RESULTSIL-17 Inhibitors

Our search yielded RCTs, some including extension trials, and clinical trials of IL-17 inhibitors used for psoriatic disease and other nonpsoriatic conditions (Table).

Risk for Deep Fungal Infection With Secukinumab
The queried studies included 20 RCTs or clinical trials along with extension trials of 3746 patients with psoriasis or other inflammatory conditions, with follow-up ranging from 12 to 52 weeks. In a 3-year extension study of SCULPTURE, Bissonnette et al¹² reported no new safety concerns for the 340 patients with moderate to severe psoriasis treated with secukinumab. Common adverse events (AEs) included nasopharyngitis, upper respiratory tract infections, and headache, but there were no reports of deep fungal infections.¹² In a subsequent 5-year analysis of 168 patients that focused on the 300-mg fixed interval treatment with secukinumab, the safety profile remained favorable, with 0 reports of invasive fungal infections.¹³ A study (FEATURE) of 118 patients with psoriasis treated with a prefilled syringe of 300 or 150 mg of secukinumab also described an acceptable safety profile and reported no deep fungal infections.¹⁴ JUNCTURE, another study utilizing autoinjectors, also found that treatment with 300 or 150 mg of secukinumab was well tolerated in 121 patients, with no deep fungal infections.¹⁵ Common AEs for both studies included nasopharyngitis and headache.^14,15 A 24-week phase 3 study for scalp psoriasis treated with secukinumab also reported 0 deep fungal infections in 51 patients.¹⁶ In an RCT comparing secukinumab and ustekinumab for moderate to severe plaque psoriasis, Blauvelt et al¹⁷ demonstrated that the incidence of serious AEs was comparable between the 2 groups, with no reports of invasive fungal infections in the 334 patients exposed to secukinumab. The CLEAR study, which compared secukinumab and ustekinumab, also found no reported deep fungal disease in the 335 patients exposed to secukinumab.¹⁸ Secukinumab exhibited a similar safety profile to ustekinumab in both studies, with common AEs being headache and nasopharyngitis.^17,18 The GESTURE study investigated the efficacy of secukinumab in 137 patients with palmoplantar psoriasis and reported a favorable profile with no reports of deep fungal disease.¹⁹ In a subanalysis of the phase 3 study ERASURE, secukinumab was shown to have a robust and sustainable efficacy in 58 Japanese patients with moderate to severe plaque psoriasis, and there were no reports of invasive fungal infections.²⁰ Another subanalysis of 36 Taiwanese patients from the ERASURE study also had similar findings, with no dose relationship observed for AEs.²¹ In a phase 2 study of 103 patients with psoriasis, Papp et al²² demonstrated AE rates that were similar across different doses of secukinumab—3×150 mg, 3×75 mg, 3×25 mg, and 1×25 mg—and described no incidences of invasive fungal disease. In a phase 2 regimen-finding study of 337 patients conducted by Rich et al,²³ the most commonly reported AEs included nasopharyngitis, worsening psoriasis, and upper respiratory tract infections, but there were no reported deep fungal infections.

Our search also resulted in studies specific to the treatment of psoriatic arthritis (PsA) with secukinumab. McInnes et al⁹ conducted a phase 2 proof-of-concept trial for patients with PsA and reported no deep fungal infections in 28 patients exposed to 10 mg/kg of secukinumab. A 2-year follow-up with the cohort from FUTURE 1, a phase 3 clinical trial, also showed no new or unexpected safety signals in 404 patients exposed to 150 or 75 mg of secukinumab, including no reports of invasive fungal disease.²⁴ FUTURE 2, a phase 3 clinical trial, demonstrated that the most common AE was upper respiratory tract infection in the 299 patients treatedwith secukinumab, but there were no recorded invasive fungal infections.²⁵ In FUTURE 3, 277 patients were treated with secukinumab, with 14 nonserious candida infections but no observed deep fungal infections.²⁶ A study comparing secukinumab to fumaric acid esters reported that 6 of 105 patients treated with secukinumab also experienced superficial candidiasis, but there were no reports of deep fungal disease.²⁷

Secukinumab also has been used in the treatment of ankylosing spondylitis in a phase 3 RCT (MEASURE 1) in which 4 cases of superficial candidiasis were reported (0.7 cases per 100 patient-years of secukinumab) that were all resolved with standard antifungal therapy.²⁸ In MEASURE 2, a 5-year phase 3 RCT, 145 patients were treated with secukinumab for ankylosing spondylitis, with common AEs including nasopharyngitis, diarrhea, and upper respiratory tract infection, but there were no reports of any invasive fungal infections.²⁹ MEASURE 3 also demonstrated similar results in which no invasive fungal infections were observed.³⁰

Risk for Deep Fungal Infection With Ixekizumab
The queried studies included 7 RCTs or clinical trials of 3523 patients with psoriasis or other inflammatory conditions, with follow-up ranging from 12 to 52 weeks. In UNCOVER-A, a phase 3 RCT of the pharmacokinetics and safety of ixekizumab, 204 patients were randomized to a prefilled syringe or autoinjector; 48% of patients experienced AEs, but no invasive fungal infections were observed.³¹ In an analysis of 3 phase 3 trials of ixekizumab including a total 2334 patients treated with ixekizumab from UNCOVER-1, UNCOVER-2, and UNCOVER-3, oral candidiasis frequently was reported, but no candidal infections met criteria for serious invasive infection.³² In UNCOVER-J, a 52-week phase 3 open-label trial of Japanese patients, 91 patients were treated for plaque psoriasis, erythrodermic psoriasis, or generalized pustular psoriasis using ixekizumab; the most common AEs included allergic reactions and injection-site reactions. One case of oral candidiasis was reported, but there were no reported cases of invasive fungal infections.³³ A comparison of ixekizumab vs ustekinumab from the IXORA-S trial demonstrated no substantial differences in AEs between the two, and no cases of deep fungal infections were reported. The most common AE between the 2 groups was nasopharyngitis.³⁴ An open-label extension over 4 years of a phase 2 RCT treated 211 patients with either 120 or 80 mg of ixekizumab; 87% of patients had experienced at least 1 AE, and all AEs were considered mild or moderate in severity, with no invasive fungal disease.³⁵

Our search also resulted in 1 study specific to the treatment of PsA with ixekizumab. A phase 3, 52-week study of patients treated with ixekizumab for PsA observed 2 incidences of oral candidiasis and nail candida infections, but no invasive fungal infections were reported.³⁶

We also found 1 study of ixekizumab used in the treatment of ankylosing spondylitis. COAST-V was a phase 3 RCT of patients treated for ankylosing spondylitis in which 164 patients were treated with ixekizumab; no serious AEs were recorded, including 0 deep fungal infections. The most common AEs observed were nasopharyngitis and upper respiratory tract infections.³⁷

Risk for Deep Fungal Infection With Brodalumab
The queried studies included 9 RCTs and 3 clinical trials along with extension trials of 1599 patients with psoriasis or other inflammatory conditions, with follow-up ranging from 12 to 120 weeks. In a phase 2 RCT of Japanese patients with moderate to severe plaque psoriasis, 113 patients were treated with 70, 140, or 210 mg of brodalumab, and the most common AEs were nasopharyngitis, diarrhea, and upper respiratory tract inflammation. There were no reported cases of fungal infections in the study.³⁸ In an open-label extension study of Japanese patients that evaluated the long-term clinical safety of brodalumab, 145 patients were enrolled and observed similar AEs to the RCT, with 7 patients experiencing oral candidiasis and 1 patient having skin candidiasis, but there were no observed deep fungal infections.³⁹ In AMG 827, which evaluated the efficacy and safety of brodalumab, 320 patients were treated, and only 2 serious AEs were reported, neither of which were deep fungal disease.¹⁰ A phase 3 RCT conducted by Papp et al⁴⁰ (AMAGINE-1) also treated 441 patients with moderate to severe plaque psoriasis with brodalumab and observed candida infections in 9 patients that were mild to moderate and responsive to treatment, with no patients discontinuing the study. In a 120-week open-label extension study of 181 patients, Papp et al⁴¹ reported 8% of patients experienced serious AEs, with 1 case of latent tuberculosis that led to withdrawal of treatment. A study also investigated the efficacy and safety of brodalumab in 30 patients with generalized pustular psoriasis or psoriatic erythroderma and observed 2 cases of mild candida infections that resolved with treatment. There were no reports of invasive fungal disease.⁴²

Our search also resulted in studies of brodalumab used in the treatment of PsA and nonpsoriatic diseases. In one phase 2 RCT, 113 patients with PsA were treated with 140 mg, 280 mg, or combined doses of brodalumab, with the most common AEs being nasopharyngitis, upper respiratory tract infection, and diarrhea, but there were no reports of deep fungal infection.⁴³ In a phase 1b trial of patients with methotrexate-resistant rheumatoid arthritis treated with brodalumab, common AEs reported included headache, cough, and abdominal pain, with only 1 case of oral candidiasis that was determined not to be drug related.⁴⁴ Finally, an RCT of patients with moderate to severe asthma treated 226 patients with brodalumab and reported a greater incidence of oral candidiasis in treatment groups compared with placebo (3.5% vs 0%) but saw no instances of invasive fungal infection.⁴⁵

IL-12/IL-23 Inhibitor

Risk for Deep Fungal Infection With Ustekinumab
The queried studies included 4 RCTs of 954 patients with psoriasis treated with ustekinumab (eTable).^46-49 Within these trials, there were no reported cases of serious infections involving deep fungal organisms during the stated follow-up period. The literature search also found long-term safety data from the ACCEPT and PHOENIX trials that included 5437 patients with psoriasis treated with ustekinumab.^66,67 There also were no demonstrated incidences of invasive fungal disease in these studies, with most cases of infection being common bacterial or viral infections.

IL-23 Inhibitors

Risk for Deep Fungal Infection With Risankizumab, Guselkumab, and Tildrakizumab
The queried studies included 16 RCTs or clinical trials for psoriatic patients treated with IL-23 inhibitors, including 5 with risankizumab,^50-54 9 with guselkumab,^55-63 and 2 with tildrakizumab.^64,65 Within these trials there were no observed cases of serious infections with deep fungal disease.

COMMENT

Our literature review has demonstrated that there does not appear to be an increased incidence of deep fungal infections for patients treated with IL-17, IL-12/IL-23, or IL-23 inhibitors for psoriatic disease. All of the reviewed studies found no cases of invasive fungal infections for patients with psoriasis treated with secukinumab, ixekizumab, brodalumab, ustekinumab, risankizumab, guselkumab, or tildrakizumab. Patients with other inflammatory conditions, such as ankylosing spondylitis, rheumatoid arthritis, and asthma, also did not appear to show an increased incidence of deep fungal disease.

Although these results show promising safety data for the use of these biologic therapies in treating inflammatory conditions, caution still is warranted, as these medications still are relatively new, with FDA approvals within the last 5 years. Safety data among different study populations also cannot be derived without further investigation, and much of the available literature is limited in long-term data. More extended trials or registry data from a large, broadly representative cohort are necessary to establish the long-term safety and risk for deep fungal infections with IL-17 and especially the newer IL-23 inhibitors.

A small percentage of patients from the reviewed literature did develop superficial candidiasis. This outcome can be expected, as the central role of IL-17 and IL-23 has been recognized in immunologic protection against infections, specifically against fungi.¹¹ Because all of the fungal infections reported for patients on IL-17 inhibitors were superficial candidiasis, guides for practical management and treatment should be implemented to standardize future research and care. A proposed screening algorithm for patients on these biologic therapies involves safety monitoring, including inspection of the oral cavity, folds, and genitals, along with inquiring about symptoms such as burning, dysgeusia, and dysuria.⁶⁸ If infection is suspected, confirmation by culture, molecular method, or optimally with esophagoscopy can be performed, and appropriate treatment may be initiated.⁶⁸ Patients with candida infections of the oral cavity, folds, or genitals can be placed on topical therapy such as nystatin, amphotericin B, ciclopirox, or other azoles, while those with infections of the esophagus can be started on oral fluconazole.⁶⁸

Although there were no reported cases of deep fungal infections, the theoretical risk for developing one while on IL-17 and IL-23 inhibitors may warrant further screening prior to beginning therapy. The TNF inhibitors approved for the treatment of psoriasis currently contain a black box warning for risk for disseminated and extrapulmonary histoplasmosis, coccidioidomycosis, blastomycosis, and other invasive fungal infections, which may highlight the importance of thorough evaluation and awareness of endemic areas for patients on biologics. Prior to initiating treatment with TNF inhibitors, current suggestions involve performing a thorough examination along with keeping a high index of suspicion for invasive fungal infections in patients who live in or have traveled to endemic regions.⁶⁹

Screening for invasive fungal infections for patients on TNF inhibitors involves questioning about potential exposures, such as demolition of old buildings, bird roosts, or spelunking.⁷⁰ Serologies or antigen testing can be used routinely, but as these tests are insensitive, empiric antifungal therapy should be initiated if there is high enough clinical suspicion.⁷¹ Currently, there are no clinical guidelines regarding fungal screening and initiation of IL-17 and IL-23 inhibitors for treatment of psoriasis and other inflammatory conditions, but careful stewardship over using these effective medications should still be practiced.

Upon review of the available safety data on the use of IL-17 and IL-23 inhibitors for the treatment of psoriasis and other inflammatory conditions, there does not appear to be an increased incidence of deep fungal infections. Physicians, however, should still be cautiously optimistic in prescribing these medications, as there is a theoretical risk for infection for all patients on biologics. A high index of suspicion for patients presenting with symptoms of fungal infections should be maintained, and appropriate diagnosis and management should be initiated if they do occur.

Psoriasis is a common chronic, multisystem, inflammatory disease with predominantly skin and joint manifestations that affects approximately 2% of the world’s population.¹ It occurs in a variety of clinical forms, from a few well-demarcated, erythematous plaques with a silvery scale to involvement of almost the entire body surface area. Beyond the debilitating physical ailments of the disease, psoriasis also may have psychosocial effects on quality of life.² The pathogenesis of psoriasis is not fully understood but represents a complex multifactorial disease with both immune-mediated and genetic components. Characterized by hyperplasia of epidermal keratinocytes, psoriasis is shown to be mediated by infiltration of T-cell lymphocytes with an increase of various inflammatory cytokines, including tumor necrosis factor (TNF) α.³ More recently, interactions of helper T cells (T_H17) via IL-17 and IL-23 have been supported to play a major role in the pathogenesis of psoriasis.^4,5

With the growing understanding of the pathophysiology of psoriasis, focused biologics have been developed to target specific cytokines implicated in the disease process and have been increasingly utilized. Tumor necrosis factor α inhibitors, including adalimumab, infliximab, and etanercept, along with the IL-12/IL-23 inhibitor ustekinumab, have been revolutionary in psoriasis treatment by providing safe and effective long-term therapy; however, there is concern of life-threatening infections with biologics because of the immunosuppressive effects and mechanisms of action.⁶ Specifically, there have been reported cases of deep fungal infections associated with TNF-α inhibitor use.⁷

Recently, the advent of IL-17 and IL-23 inhibitors has garnered notable interest in these biologics as promising treatments for psoriasis. With IL-17 and IL-23 supported to have a major role in the pathogenesis of psoriasis, targeting the cytokine is not only logical but also has proven to be effacacious.^8-10 Secukinumab, ixekizumab, and brodalumab are IL-17 inhibitors that have been approved by the US Food and Drug Administration (FDA) for the treatment of psoriasis. Secukinumab and ixekizumab are anti–IL-17A monoclonal antibodies, whereas brodalumab is an anti–IL-17 receptor antibody. Risankizumab, guselkumab, and tildrakizumab are IL-23 inhibitors that also have been approved by the FDA for the treatment of psoriasis. As with older biologics, there is concern over the safety of these inhibitors because of the central role of IL-17 and IL-23 in both innate and adaptive immune responses, particularly against fungi.¹¹ Therefore, use of biologics targeting IL-17 and IL-23 may increase susceptibility to deep fungal infections.

Safety data and discussion of the risk for deep fungal infections from IL-17, IL-12/IL-23, and IL-23 inhibitor use for psoriasis treatment currently are lacking. Given the knowledge gap, we sought to synthesize and review the current evidence on risks for deep fungal infections during biologic therapy in patients with psoriasis, with a focus on IL-17 inhibitor therapies.

METHODS

A PubMed search of articles indexed for MEDLINE from database inception to 2019 (1946-2019) was performed to find randomized controlled trials (RCTs), including extended trials and clinical trials, for IL-17, IL-12/IL-23, and IL-23 inhibitors approved by the FDA for psoriasis treatment. The following keywords were used: psoriasis or inflammatory disease and secukinumab, ixekizumab, brodalumab, ustekinumab, risankizumab, guselkumab, or tildrakizumab. Studies were restricted to the English-language literature, and those that did not provide adequate safety data on the specific types of infections that occurred were excluded.

RESULTSIL-17 Inhibitors

Our search yielded RCTs, some including extension trials, and clinical trials of IL-17 inhibitors used for psoriatic disease and other nonpsoriatic conditions (Table).

Risk for Deep Fungal Infection With Secukinumab
The queried studies included 20 RCTs or clinical trials along with extension trials of 3746 patients with psoriasis or other inflammatory conditions, with follow-up ranging from 12 to 52 weeks. In a 3-year extension study of SCULPTURE, Bissonnette et al¹² reported no new safety concerns for the 340 patients with moderate to severe psoriasis treated with secukinumab. Common adverse events (AEs) included nasopharyngitis, upper respiratory tract infections, and headache, but there were no reports of deep fungal infections.¹² In a subsequent 5-year analysis of 168 patients that focused on the 300-mg fixed interval treatment with secukinumab, the safety profile remained favorable, with 0 reports of invasive fungal infections.¹³ A study (FEATURE) of 118 patients with psoriasis treated with a prefilled syringe of 300 or 150 mg of secukinumab also described an acceptable safety profile and reported no deep fungal infections.¹⁴ JUNCTURE, another study utilizing autoinjectors, also found that treatment with 300 or 150 mg of secukinumab was well tolerated in 121 patients, with no deep fungal infections.¹⁵ Common AEs for both studies included nasopharyngitis and headache.^14,15 A 24-week phase 3 study for scalp psoriasis treated with secukinumab also reported 0 deep fungal infections in 51 patients.¹⁶ In an RCT comparing secukinumab and ustekinumab for moderate to severe plaque psoriasis, Blauvelt et al¹⁷ demonstrated that the incidence of serious AEs was comparable between the 2 groups, with no reports of invasive fungal infections in the 334 patients exposed to secukinumab. The CLEAR study, which compared secukinumab and ustekinumab, also found no reported deep fungal disease in the 335 patients exposed to secukinumab.¹⁸ Secukinumab exhibited a similar safety profile to ustekinumab in both studies, with common AEs being headache and nasopharyngitis.^17,18 The GESTURE study investigated the efficacy of secukinumab in 137 patients with palmoplantar psoriasis and reported a favorable profile with no reports of deep fungal disease.¹⁹ In a subanalysis of the phase 3 study ERASURE, secukinumab was shown to have a robust and sustainable efficacy in 58 Japanese patients with moderate to severe plaque psoriasis, and there were no reports of invasive fungal infections.²⁰ Another subanalysis of 36 Taiwanese patients from the ERASURE study also had similar findings, with no dose relationship observed for AEs.²¹ In a phase 2 study of 103 patients with psoriasis, Papp et al²² demonstrated AE rates that were similar across different doses of secukinumab—3×150 mg, 3×75 mg, 3×25 mg, and 1×25 mg—and described no incidences of invasive fungal disease. In a phase 2 regimen-finding study of 337 patients conducted by Rich et al,²³ the most commonly reported AEs included nasopharyngitis, worsening psoriasis, and upper respiratory tract infections, but there were no reported deep fungal infections.

Our search also resulted in studies specific to the treatment of psoriatic arthritis (PsA) with secukinumab. McInnes et al⁹ conducted a phase 2 proof-of-concept trial for patients with PsA and reported no deep fungal infections in 28 patients exposed to 10 mg/kg of secukinumab. A 2-year follow-up with the cohort from FUTURE 1, a phase 3 clinical trial, also showed no new or unexpected safety signals in 404 patients exposed to 150 or 75 mg of secukinumab, including no reports of invasive fungal disease.²⁴ FUTURE 2, a phase 3 clinical trial, demonstrated that the most common AE was upper respiratory tract infection in the 299 patients treatedwith secukinumab, but there were no recorded invasive fungal infections.²⁵ In FUTURE 3, 277 patients were treated with secukinumab, with 14 nonserious candida infections but no observed deep fungal infections.²⁶ A study comparing secukinumab to fumaric acid esters reported that 6 of 105 patients treated with secukinumab also experienced superficial candidiasis, but there were no reports of deep fungal disease.²⁷

Secukinumab also has been used in the treatment of ankylosing spondylitis in a phase 3 RCT (MEASURE 1) in which 4 cases of superficial candidiasis were reported (0.7 cases per 100 patient-years of secukinumab) that were all resolved with standard antifungal therapy.²⁸ In MEASURE 2, a 5-year phase 3 RCT, 145 patients were treated with secukinumab for ankylosing spondylitis, with common AEs including nasopharyngitis, diarrhea, and upper respiratory tract infection, but there were no reports of any invasive fungal infections.²⁹ MEASURE 3 also demonstrated similar results in which no invasive fungal infections were observed.³⁰

Risk for Deep Fungal Infection With Ixekizumab
The queried studies included 7 RCTs or clinical trials of 3523 patients with psoriasis or other inflammatory conditions, with follow-up ranging from 12 to 52 weeks. In UNCOVER-A, a phase 3 RCT of the pharmacokinetics and safety of ixekizumab, 204 patients were randomized to a prefilled syringe or autoinjector; 48% of patients experienced AEs, but no invasive fungal infections were observed.³¹ In an analysis of 3 phase 3 trials of ixekizumab including a total 2334 patients treated with ixekizumab from UNCOVER-1, UNCOVER-2, and UNCOVER-3, oral candidiasis frequently was reported, but no candidal infections met criteria for serious invasive infection.³² In UNCOVER-J, a 52-week phase 3 open-label trial of Japanese patients, 91 patients were treated for plaque psoriasis, erythrodermic psoriasis, or generalized pustular psoriasis using ixekizumab; the most common AEs included allergic reactions and injection-site reactions. One case of oral candidiasis was reported, but there were no reported cases of invasive fungal infections.³³ A comparison of ixekizumab vs ustekinumab from the IXORA-S trial demonstrated no substantial differences in AEs between the two, and no cases of deep fungal infections were reported. The most common AE between the 2 groups was nasopharyngitis.³⁴ An open-label extension over 4 years of a phase 2 RCT treated 211 patients with either 120 or 80 mg of ixekizumab; 87% of patients had experienced at least 1 AE, and all AEs were considered mild or moderate in severity, with no invasive fungal disease.³⁵

Our search also resulted in 1 study specific to the treatment of PsA with ixekizumab. A phase 3, 52-week study of patients treated with ixekizumab for PsA observed 2 incidences of oral candidiasis and nail candida infections, but no invasive fungal infections were reported.³⁶

We also found 1 study of ixekizumab used in the treatment of ankylosing spondylitis. COAST-V was a phase 3 RCT of patients treated for ankylosing spondylitis in which 164 patients were treated with ixekizumab; no serious AEs were recorded, including 0 deep fungal infections. The most common AEs observed were nasopharyngitis and upper respiratory tract infections.³⁷

Risk for Deep Fungal Infection With Brodalumab
The queried studies included 9 RCTs and 3 clinical trials along with extension trials of 1599 patients with psoriasis or other inflammatory conditions, with follow-up ranging from 12 to 120 weeks. In a phase 2 RCT of Japanese patients with moderate to severe plaque psoriasis, 113 patients were treated with 70, 140, or 210 mg of brodalumab, and the most common AEs were nasopharyngitis, diarrhea, and upper respiratory tract inflammation. There were no reported cases of fungal infections in the study.³⁸ In an open-label extension study of Japanese patients that evaluated the long-term clinical safety of brodalumab, 145 patients were enrolled and observed similar AEs to the RCT, with 7 patients experiencing oral candidiasis and 1 patient having skin candidiasis, but there were no observed deep fungal infections.³⁹ In AMG 827, which evaluated the efficacy and safety of brodalumab, 320 patients were treated, and only 2 serious AEs were reported, neither of which were deep fungal disease.¹⁰ A phase 3 RCT conducted by Papp et al⁴⁰ (AMAGINE-1) also treated 441 patients with moderate to severe plaque psoriasis with brodalumab and observed candida infections in 9 patients that were mild to moderate and responsive to treatment, with no patients discontinuing the study. In a 120-week open-label extension study of 181 patients, Papp et al⁴¹ reported 8% of patients experienced serious AEs, with 1 case of latent tuberculosis that led to withdrawal of treatment. A study also investigated the efficacy and safety of brodalumab in 30 patients with generalized pustular psoriasis or psoriatic erythroderma and observed 2 cases of mild candida infections that resolved with treatment. There were no reports of invasive fungal disease.⁴²

Our search also resulted in studies of brodalumab used in the treatment of PsA and nonpsoriatic diseases. In one phase 2 RCT, 113 patients with PsA were treated with 140 mg, 280 mg, or combined doses of brodalumab, with the most common AEs being nasopharyngitis, upper respiratory tract infection, and diarrhea, but there were no reports of deep fungal infection.⁴³ In a phase 1b trial of patients with methotrexate-resistant rheumatoid arthritis treated with brodalumab, common AEs reported included headache, cough, and abdominal pain, with only 1 case of oral candidiasis that was determined not to be drug related.⁴⁴ Finally, an RCT of patients with moderate to severe asthma treated 226 patients with brodalumab and reported a greater incidence of oral candidiasis in treatment groups compared with placebo (3.5% vs 0%) but saw no instances of invasive fungal infection.⁴⁵

IL-12/IL-23 Inhibitor

Risk for Deep Fungal Infection With Ustekinumab
The queried studies included 4 RCTs of 954 patients with psoriasis treated with ustekinumab (eTable).^46-49 Within these trials, there were no reported cases of serious infections involving deep fungal organisms during the stated follow-up period. The literature search also found long-term safety data from the ACCEPT and PHOENIX trials that included 5437 patients with psoriasis treated with ustekinumab.^66,67 There also were no demonstrated incidences of invasive fungal disease in these studies, with most cases of infection being common bacterial or viral infections.

IL-23 Inhibitors

Risk for Deep Fungal Infection With Risankizumab, Guselkumab, and Tildrakizumab
The queried studies included 16 RCTs or clinical trials for psoriatic patients treated with IL-23 inhibitors, including 5 with risankizumab,^50-54 9 with guselkumab,^55-63 and 2 with tildrakizumab.^64,65 Within these trials there were no observed cases of serious infections with deep fungal disease.

COMMENT

Our literature review has demonstrated that there does not appear to be an increased incidence of deep fungal infections for patients treated with IL-17, IL-12/IL-23, or IL-23 inhibitors for psoriatic disease. All of the reviewed studies found no cases of invasive fungal infections for patients with psoriasis treated with secukinumab, ixekizumab, brodalumab, ustekinumab, risankizumab, guselkumab, or tildrakizumab. Patients with other inflammatory conditions, such as ankylosing spondylitis, rheumatoid arthritis, and asthma, also did not appear to show an increased incidence of deep fungal disease.

Although these results show promising safety data for the use of these biologic therapies in treating inflammatory conditions, caution still is warranted, as these medications still are relatively new, with FDA approvals within the last 5 years. Safety data among different study populations also cannot be derived without further investigation, and much of the available literature is limited in long-term data. More extended trials or registry data from a large, broadly representative cohort are necessary to establish the long-term safety and risk for deep fungal infections with IL-17 and especially the newer IL-23 inhibitors.

A small percentage of patients from the reviewed literature did develop superficial candidiasis. This outcome can be expected, as the central role of IL-17 and IL-23 has been recognized in immunologic protection against infections, specifically against fungi.¹¹ Because all of the fungal infections reported for patients on IL-17 inhibitors were superficial candidiasis, guides for practical management and treatment should be implemented to standardize future research and care. A proposed screening algorithm for patients on these biologic therapies involves safety monitoring, including inspection of the oral cavity, folds, and genitals, along with inquiring about symptoms such as burning, dysgeusia, and dysuria.⁶⁸ If infection is suspected, confirmation by culture, molecular method, or optimally with esophagoscopy can be performed, and appropriate treatment may be initiated.⁶⁸ Patients with candida infections of the oral cavity, folds, or genitals can be placed on topical therapy such as nystatin, amphotericin B, ciclopirox, or other azoles, while those with infections of the esophagus can be started on oral fluconazole.⁶⁸

Although there were no reported cases of deep fungal infections, the theoretical risk for developing one while on IL-17 and IL-23 inhibitors may warrant further screening prior to beginning therapy. The TNF inhibitors approved for the treatment of psoriasis currently contain a black box warning for risk for disseminated and extrapulmonary histoplasmosis, coccidioidomycosis, blastomycosis, and other invasive fungal infections, which may highlight the importance of thorough evaluation and awareness of endemic areas for patients on biologics. Prior to initiating treatment with TNF inhibitors, current suggestions involve performing a thorough examination along with keeping a high index of suspicion for invasive fungal infections in patients who live in or have traveled to endemic regions.⁶⁹

Screening for invasive fungal infections for patients on TNF inhibitors involves questioning about potential exposures, such as demolition of old buildings, bird roosts, or spelunking.⁷⁰ Serologies or antigen testing can be used routinely, but as these tests are insensitive, empiric antifungal therapy should be initiated if there is high enough clinical suspicion.⁷¹ Currently, there are no clinical guidelines regarding fungal screening and initiation of IL-17 and IL-23 inhibitors for treatment of psoriasis and other inflammatory conditions, but careful stewardship over using these effective medications should still be practiced.

Upon review of the available safety data on the use of IL-17 and IL-23 inhibitors for the treatment of psoriasis and other inflammatory conditions, there does not appear to be an increased incidence of deep fungal infections. Physicians, however, should still be cautiously optimistic in prescribing these medications, as there is a theoretical risk for infection for all patients on biologics. A high index of suspicion for patients presenting with symptoms of fungal infections should be maintained, and appropriate diagnosis and management should be initiated if they do occur.

Patrick J. Culligan, MD: We all know that burnout is an important problem among surgeons. In fact, it seems that, in the United States, we are working longer hours than ever before, and that higher education correlates with less balance in life. This dysfunction seems to start in school, when we are encouraged to be competitive, and overwork just becomes another way to compete. It’s very easy to get swept up in the traditional model of academic medicine, the engine of which is competition and overwork.

My impression of our younger colleagues, however, is that many of them are not attracted to the traditional ivory tower research model of academic advancement to which many in previous generations aspired. They seem more concerned with work-life balance as their measure of success rather than the classic metrics of money and prestige. Everyone still needs role models and mentors, though, and that’s where all of you come in. I asked each of you to be on this panel because I admire you for your varying approaches to work-life balance while achieving success as gynecologic surgeons. I thought others in the field might be inspired by hearing your stories.

Cultivating your passions

Kristie Greene, MD: What I have come to learn and appreciate is a really simple point: you do not have to do everything. Determining who you want to be both personally and professionally is step 1.

Granted, answering the question, “Who do I want to be?” is not as simple as it sounds. Many factors figure into the decisions we make in our personal and professional lives. Also, it is not a question we often stop and ask ourselves. From early on, we are placed on an escalator moving up through medical school, residency, fellowship, good job, better job, etc. We are so accustomed to being competitive, to winning, and to wanting to be the best that we sometimes forget to ask ourselves, “What is it exactly that I want, and why? What is my endpoint? And does it make me happy?”

Multitasking is regarded as a talent. As much as we would like to believe that we can do everything at the same time and do it all well, we actually can’t. A friend of mine made me read a book a couple of years ago, called Feeling Good, by David Burns. The book encourages you to consider the different tasks you do in a day and rate how good you are at each of them on a scale of 1 to 10. It then asks you to think about how much enjoyment you derive from each of the tasks and about why you are doing the ones that bring you little to no enjoyment.

I ultimately decided that, for me professionally, the most important thing was my interest in global health. So I decided to do whatever it took to make this happen. But you don’t get something for nothing, and everything comes with sacrifices.

Continue to: Charles Rardin, MD...

Charles Rardin, MD: How exactly did you decide that you were going to focus your career toward pursuing international health? How did you know it was more important? And how did you overcome some of those obstacles?

Dr. Greene: You have to ask the hard question again about what brings you the most joy professionally and personally. That was the easy part of it for me because global health has always been that source of happiness and fulfillment for me. The more challenging parts are the sacrifices and hard choices that come with it. With global health, it can be difficult to balance the demands of a clinical practice.

All of our jobs are a business. I am still struggling with the money part of it. For my husband and I, that meant we had to start small—do what we could afford. But then it blossomed into something that was involving residents, fellows, and med students, which requires far more funding than we had. So I reached out to family. Most of our families donate to different organizations or charities every year, so why not donate to a loved one for something they are passionate about?

At the University of South Florida (USF), we set up a fund, a foundation for global health, which helps support our work abroad as well as the costs associated with involvement of our trainees. Right now, what we have is still small potatoes to a country, but we are making it happen by starting at a small level and growing it.

Beyond the money aspect, traveling abroad means less involvement in meetings, missed opportunities to teach courses that might interest me, and time away from my family. I guess my advice on this whole thing is that you can make things happen if they are important enough to you, and if you are willing to make sacrifices in other areas because you can’t have it all.

Making time for you

Dr. Culligan: So you have found what is important to you, and you have found a way to make it happen. But you are faced with more work; you have given yourself additional work on top of your regular work. How do you make time for a personal life?

Catherine Matthews, MD: In preparing for this discussion, I decided to break down my advice into 3 buckets: The first bucket is discovering and knowing your authentic self. The second is building a community, which I’ll elaborate on. And the third, which we have discussed, is to let go of the money.

Dr. Culligan: I love the concept of the authentic self, but how does that jive with a tendency to strive for perfection? We all think we can do it all. How do we narrow down to what really matters?

Dr. Matthews: We often focus on the things that bring us happiness and what we are good at, but it’s the things that make us unhappy that tend to bring us down. It’s the presence of unhappiness, not the absence of happiness, that seems to be the undoing of many, including myself.

None of us are born with dramatic insight. It is experience that leads to insight. People who are actually present are able to gain insight through observation. A person becomes a better surgeon by observing the outcome of doing a stitch this way versus that; you learn how to do it by seeing what it looks like afterward.

Finding our authentic selves happens in much the same way. Having the presence of mind to ask the right questions, such as, “How am I feeling while I’m doing this?” leads to insights into the true self.

Continue to: It takes a village...

Dr. Greene: Catherine mentioned community earlier, and that is extremely important. The people who surround us can have a huge impact on the way we perceive things, including ourselves. Having a mix of people in our lives—some who practice medicine and others who don’t—helps us stay balanced and answer some of the tough questions. Catherine, for example, has helped me in various stages of my career to ask myself meaningful questions and get real answers.

Dr. Rardin: Part of finding balance is luck, and part of it is making a choice between money and everything else. In considering my first job out of training, I knew that money had the potential to distract me from what was important to me. So I chose a position that was almost entirely salaried so that the decisions I made clinically, surgically, and regarding work-life balance would be less likely to directly impact what was important to me.

Sally Huber, MD: I am still in the “getting there” phase of my life, but one thing I have found is that getting my family involved and excited about what I do has made them much more accepting of when I have longer work days or work to do on the weekend. My spouse has become quite involved with what I have been doing with transgender health in Atlanta. It has been a great bonding experience; she shares my passions, and together we are creating something about which we both can be proud.

When work invades home life

Dr. Culligan: That is great. Sally, I think when we talked, you were just learning about the necessity of mental separation and of not taking your work home with you, which is so hard for all of us with all of our devices.

Dr. Huber: Yes, this year has been about seeing what works best as far as being efficient at work and having quality time at home. At the end of every day I ask myself, “What worked well today? What didn’t work well? What else can I do to maximize time with my family?” I am slowly becoming more efficient, but it has been a challenge. During fellowship, your day is pretty set, but once you are practicing on your own, your hours and responsibilities are completely different, and you have to figure out what works best for you, your values, and your expectations of private life. It takes some time, and I am still figuring it out.

Dr. Culligan: How often would you say that you bring work home? I try hard once I am home to quit working, but sometimes on the weekends I break that rule.

Dr. Matthews: I must say that I do feel like there are certain times when I am better at that than others. Work comes in waves with pressing deadlines. If I averaged it out, probably a third of the time I have some email or some conference call or something that I have got to do at home. I do really try to limit the obligations that I have after 5:30 or 6:00 pm. I resent intrusions after that time. As far as weekends, I delegate about one weekend every 2 months to work, instead of doing a little bit every weekend.

Dr. Greene: I agree. I try hard to make 5:30 to 7:30 pm unequivocal time for a family dinner and time for my kids. During that time, I do not have my phone near me so I can’t look at email or texts. I try not to schedule conference calls. I try to be there to read books to my kids at night. Then if I need to do work, I do it later at night, which interferes with time with my spouse, and is not ideal, but that’s what happens.

Dr. Matthews: One of the things that I think is a huge part of work-life balance is work-related travel. When you are present at work on a consistent basis, the work does not pile up to the extent that it does when you are absent on a trip. When you come back, you invariably pay the price by seeing more patients and doing more surgery. Then it becomes a stressful event.

My advice to young people is to be very thoughtful about planning trips, especially distant ones. You do not want to sit on a plane all day when you could be doing something more productive. If I could have done something differently in my mid-career, I would have traveled less.

Continue to: Prioritizing “out of office” time...

Dr. Greene: How do you all mentally separate yourself from work, so that when you are on vacation with your family you are not thinking about the office, the patients, and all of the things on your to-do list?

Dr. Rardin: I don’t have a great answer for that except that it is about being present. You have to decide that now is the time when I am home, now is the time when I am a parent, now is the time when I am a boy scout leader, etc. I guess maybe it’s a skill, or maybe it’s about making something a priority. Work will always be waiting for you when you turn your attention back to it.

Dr. Matthews: Kristie, the answer to your question goes back to community. Partners in a practice cover for each other. You have to trust them to take care of things so that you can relax during your time away.

Some people recommend not scheduling challenging cases right before going away because invariably something goes wrong, and then you are asking, “Why did I schedule 3 colpopexies before getting on a plane?”

Dr. Rardin: Yes, I completely agree with all of that. Personally, I feel fortunate that I can compartmentalize pretty well. When I am home with my kids, I allow myself to shed some of the doctor/surgeon/leadership persona; I am able to be goofy and completely non–doctor-like. It works to help me leave work behind.

Dr. Matthews: Other things you can do include setting up an out-of-office notice on your email that says when you will be back and what to do in case of urgent matters. This basically says to the world, “Don’t expect to hear from me until X date.” It removes the expectation that you will respond sooner. Otherwise, we would all be on our smartphones all the time and not enjoying our time away.

What I wish I knew then

Dr. Culligan: How would you complete the sentence, “I wish they had told me X when I was embarking on my career?”

Dr. Rardin: I keep coming back to the phrase, “Don’t do anything that you can reasonably pay someone else to do.” By that I mean, if you don’t get energy from housework, consider spending some of your money to get help with the housework. Resolve to make a relatively small expenditure to maximize the quality of the time that you give to yourself and your family. Those are the sorts of things that I think can go a long way.

Dr. Culligan: Charley, your wife is an ObGyn. How do you navigate a dual medical career household? What advice do you have for others?

Dr. Rardin: When I was going into fellowship, we had a conversation about how hard it is for both people in a relationship to have an academic fire in the belly and to be truly engaged in climbing the academic ladder. We made a decision that Jane would go into private practice. There has got to be some give and take in a dual medical relationship; a lot of sacrifices and compromises need to happen. We are fortunate in that there are complementary aspects to our jobs. We both spend about the same number of nights away from the house, but my travel is more in chunks and hers is overnight calls for labor and delivery. We have different ways of (briefly) single-parenting, and you have to come up with ways to handle the domestic chores.

Dr. Matthews: I wish someone had explained to me that the people you work with are much more important than the place. The human connection is what defines your experience, much more than any ego-driven outcome.

Dr. Greene: I wish someone had explained to me the competing aspects of academic medicine. The cards are stacked in a way that make it difficult for you to win. For example, you may love to teach and may be really good at it, but if you let your students handle too many cases, your relative value units plummet and then the hospital is on your back. There are the interests of people, and there are the interests of the business. Everything is a balance, and it’s really tricky.

Dr. Huber: Luckily, Pat counselled me as I was finishing my fellowship about the importance of negotiating a good contract, of being pushy and knowing what you want out of it and knowing what your limitations are. I joined a private practice that had 3 different physical locations. If I had to drive to all of them, as they wanted, it would have meant up to a one-and-a-half-hour commute. But I pushed to stay in one location and to put that extra hour to better use. I am glad I did, but it was terrifying at the time because I didn’t want to lose the offer. I know people that did not do that and took the first thing they got. Now, they are driving all over the place or they have these crazy hours or terrible call responsibilities that if they had just been a little firmer, they probably could have gotten out of. As they start trying to find work-life balance, they are already handicapped.

Continue to: Passions outside the office...

Passions outside the office

Dr. Culligan: One thing I would like to touch on is what is going on in each of your personal lives because all of you have interesting stories to tell outside of what you do professionally. What drives you other than medicine?

Dr. Rardin: I am the father of 3 boys. The oldest one just got his Eagle Scout rank yesterday in Boy Scouts. I would be a woodworker if I wasn’t in medicine. I am a Deacon at church. And I love to spend my downtime reading with my family in front of the fireplace.

Dr. Matthews: For me, it’s music. When my husband and I first met, he asked me if I played a musical instrument. I said I played the cello in primary school. He said, “Great, go rent a cello.” I was never at all interested in playing the cello by myself, but because he plays guitar and piano we became able to play a lot of music together. Our son, Alexander, plays drums. We now have a family band.

In addition, I do yoga. I would never have labeled myself an anxious person, but I learned through this process that I am and need to manage it. It took a lot of years to figure that out. If I don’t leave myself an hour each day to go to a yoga class, I am not a happy person and neither is anyone around me. Also, I get tremendous pleasure from reading books and magazines as opposed to watching a screen.

Dr. Greene: I have found that my passions outside of work often change depending on my stage of life. Right now, I have two young babies and so my life outside of work revolves around them. Before the babies, my dad, who lives in Buffalo, was ill. So for awhile, we were flying to Buffalo almost every weekend that I was not on call. I would say, in general what fuels me is connecting with the people I love as often as I can. A typical night involves me and my husband going for a walk with our kids and dog after dinner and talking to each other. We connect with neighbors and chat on the front porch. It doesn’t really matter what we are doing; it is about being surrounded by people who matter.

Dr. Huber: It’s similar for me. Having a child completely shifts your world view. My goal every day is to give my daughter her first feeding in the morning and to get home as soon as possible at the end of the day to do her last feeding and put her to sleep. She crawled for the first time yesterday, and I was so excited that I could be there for that.

Also, I love being outdoors. I love hiking and camping. Going on a hike and being outside with nature is my way of decompressing.

Continue to: Thinking about upcoming generations...

Dr. Matthews: One other thing I would like to propose is looking at what can we do to make the profession better for the next generation. As a group, our profession is somewhat inflexible. We tend to fall into the trap of, “since this is the way we have always done it this is how we should continue doing it.” The OR still starts at 7:00 or 7:30 am, ignoring the need for school drop-offs, etc. We are not innovative about flexibility in the work week. Honestly, it does not work well for many people, patients and physicians alike. Flexible scheduling should be something that is on the table for both men and women who are trying to balance being full-time parents and full-time surgeons. We need to create an environment in which it is okay for you to spend 10 years instead of 6 as an assistant professor because you are also a young parent, and it will not count against you when you come up for promotion.

Dr. Culligan: I agree with you, Catherine. Full “Professor” is a nice title, but it means time away from family and a lot of other things. Each of us has to decide whether it is worth it, especially since it often does not come with any extra money.

Dr. Huber: A question on a recent survey of residents asked, “Do you see yourself going into private practice or academic medicine when you’ve completed your residency?” When I was a resident, everyone wanted to go into academic medicine, but now it seems like more and more residents have their sights set on private practice because that is where they see the opportunities to create work-life balance.

In the academic world, you have to try to get a promotion in X number of years, and get X number of publications, and be a great teacher, doctor, and administrator all at the same time. I am wondering if we are going to start seeing more and more residents and fellows going into private or hospital-owned practice where there aren’t those added expectations.

Dr. Rardin: I agree, and we are back to what we said in the beginning about doing an honest assessment of what is meaningful and important. We are all trained to try to reach for that shiny brass ring, but do we really want that brass ring? Will it be an asset or a hindrance once we get it? It is okay to be honest and say, “I really don’t want that promotion. I would rather spend more time with my family.” ●

Patrick J. Culligan, MD: We all know that burnout is an important problem among surgeons. In fact, it seems that, in the United States, we are working longer hours than ever before, and that higher education correlates with less balance in life. This dysfunction seems to start in school, when we are encouraged to be competitive, and overwork just becomes another way to compete. It’s very easy to get swept up in the traditional model of academic medicine, the engine of which is competition and overwork.

My impression of our younger colleagues, however, is that many of them are not attracted to the traditional ivory tower research model of academic advancement to which many in previous generations aspired. They seem more concerned with work-life balance as their measure of success rather than the classic metrics of money and prestige. Everyone still needs role models and mentors, though, and that’s where all of you come in. I asked each of you to be on this panel because I admire you for your varying approaches to work-life balance while achieving success as gynecologic surgeons. I thought others in the field might be inspired by hearing your stories.

Cultivating your passions

Kristie Greene, MD: What I have come to learn and appreciate is a really simple point: you do not have to do everything. Determining who you want to be both personally and professionally is step 1.

Granted, answering the question, “Who do I want to be?” is not as simple as it sounds. Many factors figure into the decisions we make in our personal and professional lives. Also, it is not a question we often stop and ask ourselves. From early on, we are placed on an escalator moving up through medical school, residency, fellowship, good job, better job, etc. We are so accustomed to being competitive, to winning, and to wanting to be the best that we sometimes forget to ask ourselves, “What is it exactly that I want, and why? What is my endpoint? And does it make me happy?”

Multitasking is regarded as a talent. As much as we would like to believe that we can do everything at the same time and do it all well, we actually can’t. A friend of mine made me read a book a couple of years ago, called Feeling Good, by David Burns. The book encourages you to consider the different tasks you do in a day and rate how good you are at each of them on a scale of 1 to 10. It then asks you to think about how much enjoyment you derive from each of the tasks and about why you are doing the ones that bring you little to no enjoyment.

I ultimately decided that, for me professionally, the most important thing was my interest in global health. So I decided to do whatever it took to make this happen. But you don’t get something for nothing, and everything comes with sacrifices.

Continue to: Charles Rardin, MD...

Charles Rardin, MD: How exactly did you decide that you were going to focus your career toward pursuing international health? How did you know it was more important? And how did you overcome some of those obstacles?

Dr. Greene: You have to ask the hard question again about what brings you the most joy professionally and personally. That was the easy part of it for me because global health has always been that source of happiness and fulfillment for me. The more challenging parts are the sacrifices and hard choices that come with it. With global health, it can be difficult to balance the demands of a clinical practice.

All of our jobs are a business. I am still struggling with the money part of it. For my husband and I, that meant we had to start small—do what we could afford. But then it blossomed into something that was involving residents, fellows, and med students, which requires far more funding than we had. So I reached out to family. Most of our families donate to different organizations or charities every year, so why not donate to a loved one for something they are passionate about?

At the University of South Florida (USF), we set up a fund, a foundation for global health, which helps support our work abroad as well as the costs associated with involvement of our trainees. Right now, what we have is still small potatoes to a country, but we are making it happen by starting at a small level and growing it.

Beyond the money aspect, traveling abroad means less involvement in meetings, missed opportunities to teach courses that might interest me, and time away from my family. I guess my advice on this whole thing is that you can make things happen if they are important enough to you, and if you are willing to make sacrifices in other areas because you can’t have it all.

Making time for you

Dr. Culligan: So you have found what is important to you, and you have found a way to make it happen. But you are faced with more work; you have given yourself additional work on top of your regular work. How do you make time for a personal life?

Catherine Matthews, MD: In preparing for this discussion, I decided to break down my advice into 3 buckets: The first bucket is discovering and knowing your authentic self. The second is building a community, which I’ll elaborate on. And the third, which we have discussed, is to let go of the money.

Dr. Culligan: I love the concept of the authentic self, but how does that jive with a tendency to strive for perfection? We all think we can do it all. How do we narrow down to what really matters?

Dr. Matthews: We often focus on the things that bring us happiness and what we are good at, but it’s the things that make us unhappy that tend to bring us down. It’s the presence of unhappiness, not the absence of happiness, that seems to be the undoing of many, including myself.

None of us are born with dramatic insight. It is experience that leads to insight. People who are actually present are able to gain insight through observation. A person becomes a better surgeon by observing the outcome of doing a stitch this way versus that; you learn how to do it by seeing what it looks like afterward.

Finding our authentic selves happens in much the same way. Having the presence of mind to ask the right questions, such as, “How am I feeling while I’m doing this?” leads to insights into the true self.

Continue to: It takes a village...

Dr. Greene: Catherine mentioned community earlier, and that is extremely important. The people who surround us can have a huge impact on the way we perceive things, including ourselves. Having a mix of people in our lives—some who practice medicine and others who don’t—helps us stay balanced and answer some of the tough questions. Catherine, for example, has helped me in various stages of my career to ask myself meaningful questions and get real answers.

Dr. Rardin: Part of finding balance is luck, and part of it is making a choice between money and everything else. In considering my first job out of training, I knew that money had the potential to distract me from what was important to me. So I chose a position that was almost entirely salaried so that the decisions I made clinically, surgically, and regarding work-life balance would be less likely to directly impact what was important to me.

Sally Huber, MD: I am still in the “getting there” phase of my life, but one thing I have found is that getting my family involved and excited about what I do has made them much more accepting of when I have longer work days or work to do on the weekend. My spouse has become quite involved with what I have been doing with transgender health in Atlanta. It has been a great bonding experience; she shares my passions, and together we are creating something about which we both can be proud.

When work invades home life

Dr. Culligan: That is great. Sally, I think when we talked, you were just learning about the necessity of mental separation and of not taking your work home with you, which is so hard for all of us with all of our devices.

Dr. Huber: Yes, this year has been about seeing what works best as far as being efficient at work and having quality time at home. At the end of every day I ask myself, “What worked well today? What didn’t work well? What else can I do to maximize time with my family?” I am slowly becoming more efficient, but it has been a challenge. During fellowship, your day is pretty set, but once you are practicing on your own, your hours and responsibilities are completely different, and you have to figure out what works best for you, your values, and your expectations of private life. It takes some time, and I am still figuring it out.

Dr. Culligan: How often would you say that you bring work home? I try hard once I am home to quit working, but sometimes on the weekends I break that rule.

Dr. Matthews: I must say that I do feel like there are certain times when I am better at that than others. Work comes in waves with pressing deadlines. If I averaged it out, probably a third of the time I have some email or some conference call or something that I have got to do at home. I do really try to limit the obligations that I have after 5:30 or 6:00 pm. I resent intrusions after that time. As far as weekends, I delegate about one weekend every 2 months to work, instead of doing a little bit every weekend.

Dr. Greene: I agree. I try hard to make 5:30 to 7:30 pm unequivocal time for a family dinner and time for my kids. During that time, I do not have my phone near me so I can’t look at email or texts. I try not to schedule conference calls. I try to be there to read books to my kids at night. Then if I need to do work, I do it later at night, which interferes with time with my spouse, and is not ideal, but that’s what happens.

Dr. Matthews: One of the things that I think is a huge part of work-life balance is work-related travel. When you are present at work on a consistent basis, the work does not pile up to the extent that it does when you are absent on a trip. When you come back, you invariably pay the price by seeing more patients and doing more surgery. Then it becomes a stressful event.

My advice to young people is to be very thoughtful about planning trips, especially distant ones. You do not want to sit on a plane all day when you could be doing something more productive. If I could have done something differently in my mid-career, I would have traveled less.

Continue to: Prioritizing “out of office” time...

Dr. Greene: How do you all mentally separate yourself from work, so that when you are on vacation with your family you are not thinking about the office, the patients, and all of the things on your to-do list?

Dr. Rardin: I don’t have a great answer for that except that it is about being present. You have to decide that now is the time when I am home, now is the time when I am a parent, now is the time when I am a boy scout leader, etc. I guess maybe it’s a skill, or maybe it’s about making something a priority. Work will always be waiting for you when you turn your attention back to it.

Dr. Matthews: Kristie, the answer to your question goes back to community. Partners in a practice cover for each other. You have to trust them to take care of things so that you can relax during your time away.

Some people recommend not scheduling challenging cases right before going away because invariably something goes wrong, and then you are asking, “Why did I schedule 3 colpopexies before getting on a plane?”

Dr. Rardin: Yes, I completely agree with all of that. Personally, I feel fortunate that I can compartmentalize pretty well. When I am home with my kids, I allow myself to shed some of the doctor/surgeon/leadership persona; I am able to be goofy and completely non–doctor-like. It works to help me leave work behind.

Dr. Matthews: Other things you can do include setting up an out-of-office notice on your email that says when you will be back and what to do in case of urgent matters. This basically says to the world, “Don’t expect to hear from me until X date.” It removes the expectation that you will respond sooner. Otherwise, we would all be on our smartphones all the time and not enjoying our time away.

What I wish I knew then

Dr. Culligan: How would you complete the sentence, “I wish they had told me X when I was embarking on my career?”

Dr. Rardin: I keep coming back to the phrase, “Don’t do anything that you can reasonably pay someone else to do.” By that I mean, if you don’t get energy from housework, consider spending some of your money to get help with the housework. Resolve to make a relatively small expenditure to maximize the quality of the time that you give to yourself and your family. Those are the sorts of things that I think can go a long way.

Dr. Culligan: Charley, your wife is an ObGyn. How do you navigate a dual medical career household? What advice do you have for others?

Dr. Rardin: When I was going into fellowship, we had a conversation about how hard it is for both people in a relationship to have an academic fire in the belly and to be truly engaged in climbing the academic ladder. We made a decision that Jane would go into private practice. There has got to be some give and take in a dual medical relationship; a lot of sacrifices and compromises need to happen. We are fortunate in that there are complementary aspects to our jobs. We both spend about the same number of nights away from the house, but my travel is more in chunks and hers is overnight calls for labor and delivery. We have different ways of (briefly) single-parenting, and you have to come up with ways to handle the domestic chores.

Dr. Matthews: I wish someone had explained to me that the people you work with are much more important than the place. The human connection is what defines your experience, much more than any ego-driven outcome.

Dr. Greene: I wish someone had explained to me the competing aspects of academic medicine. The cards are stacked in a way that make it difficult for you to win. For example, you may love to teach and may be really good at it, but if you let your students handle too many cases, your relative value units plummet and then the hospital is on your back. There are the interests of people, and there are the interests of the business. Everything is a balance, and it’s really tricky.

Dr. Huber: Luckily, Pat counselled me as I was finishing my fellowship about the importance of negotiating a good contract, of being pushy and knowing what you want out of it and knowing what your limitations are. I joined a private practice that had 3 different physical locations. If I had to drive to all of them, as they wanted, it would have meant up to a one-and-a-half-hour commute. But I pushed to stay in one location and to put that extra hour to better use. I am glad I did, but it was terrifying at the time because I didn’t want to lose the offer. I know people that did not do that and took the first thing they got. Now, they are driving all over the place or they have these crazy hours or terrible call responsibilities that if they had just been a little firmer, they probably could have gotten out of. As they start trying to find work-life balance, they are already handicapped.

Continue to: Passions outside the office...

Passions outside the office

Dr. Culligan: One thing I would like to touch on is what is going on in each of your personal lives because all of you have interesting stories to tell outside of what you do professionally. What drives you other than medicine?

Dr. Rardin: I am the father of 3 boys. The oldest one just got his Eagle Scout rank yesterday in Boy Scouts. I would be a woodworker if I wasn’t in medicine. I am a Deacon at church. And I love to spend my downtime reading with my family in front of the fireplace.

Dr. Matthews: For me, it’s music. When my husband and I first met, he asked me if I played a musical instrument. I said I played the cello in primary school. He said, “Great, go rent a cello.” I was never at all interested in playing the cello by myself, but because he plays guitar and piano we became able to play a lot of music together. Our son, Alexander, plays drums. We now have a family band.

In addition, I do yoga. I would never have labeled myself an anxious person, but I learned through this process that I am and need to manage it. It took a lot of years to figure that out. If I don’t leave myself an hour each day to go to a yoga class, I am not a happy person and neither is anyone around me. Also, I get tremendous pleasure from reading books and magazines as opposed to watching a screen.

Dr. Greene: I have found that my passions outside of work often change depending on my stage of life. Right now, I have two young babies and so my life outside of work revolves around them. Before the babies, my dad, who lives in Buffalo, was ill. So for awhile, we were flying to Buffalo almost every weekend that I was not on call. I would say, in general what fuels me is connecting with the people I love as often as I can. A typical night involves me and my husband going for a walk with our kids and dog after dinner and talking to each other. We connect with neighbors and chat on the front porch. It doesn’t really matter what we are doing; it is about being surrounded by people who matter.

Dr. Huber: It’s similar for me. Having a child completely shifts your world view. My goal every day is to give my daughter her first feeding in the morning and to get home as soon as possible at the end of the day to do her last feeding and put her to sleep. She crawled for the first time yesterday, and I was so excited that I could be there for that.

Also, I love being outdoors. I love hiking and camping. Going on a hike and being outside with nature is my way of decompressing.

Continue to: Thinking about upcoming generations...

Dr. Matthews: One other thing I would like to propose is looking at what can we do to make the profession better for the next generation. As a group, our profession is somewhat inflexible. We tend to fall into the trap of, “since this is the way we have always done it this is how we should continue doing it.” The OR still starts at 7:00 or 7:30 am, ignoring the need for school drop-offs, etc. We are not innovative about flexibility in the work week. Honestly, it does not work well for many people, patients and physicians alike. Flexible scheduling should be something that is on the table for both men and women who are trying to balance being full-time parents and full-time surgeons. We need to create an environment in which it is okay for you to spend 10 years instead of 6 as an assistant professor because you are also a young parent, and it will not count against you when you come up for promotion.

Dr. Culligan: I agree with you, Catherine. Full “Professor” is a nice title, but it means time away from family and a lot of other things. Each of us has to decide whether it is worth it, especially since it often does not come with any extra money.

Dr. Huber: A question on a recent survey of residents asked, “Do you see yourself going into private practice or academic medicine when you’ve completed your residency?” When I was a resident, everyone wanted to go into academic medicine, but now it seems like more and more residents have their sights set on private practice because that is where they see the opportunities to create work-life balance.

In the academic world, you have to try to get a promotion in X number of years, and get X number of publications, and be a great teacher, doctor, and administrator all at the same time. I am wondering if we are going to start seeing more and more residents and fellows going into private or hospital-owned practice where there aren’t those added expectations.

Dr. Rardin: I agree, and we are back to what we said in the beginning about doing an honest assessment of what is meaningful and important. We are all trained to try to reach for that shiny brass ring, but do we really want that brass ring? Will it be an asset or a hindrance once we get it? It is okay to be honest and say, “I really don’t want that promotion. I would rather spend more time with my family.” ●

Patrick J. Culligan, MD: We all know that burnout is an important problem among surgeons. In fact, it seems that, in the United States, we are working longer hours than ever before, and that higher education correlates with less balance in life. This dysfunction seems to start in school, when we are encouraged to be competitive, and overwork just becomes another way to compete. It’s very easy to get swept up in the traditional model of academic medicine, the engine of which is competition and overwork.

My impression of our younger colleagues, however, is that many of them are not attracted to the traditional ivory tower research model of academic advancement to which many in previous generations aspired. They seem more concerned with work-life balance as their measure of success rather than the classic metrics of money and prestige. Everyone still needs role models and mentors, though, and that’s where all of you come in. I asked each of you to be on this panel because I admire you for your varying approaches to work-life balance while achieving success as gynecologic surgeons. I thought others in the field might be inspired by hearing your stories.

Cultivating your passions

Kristie Greene, MD: What I have come to learn and appreciate is a really simple point: you do not have to do everything. Determining who you want to be both personally and professionally is step 1.

Granted, answering the question, “Who do I want to be?” is not as simple as it sounds. Many factors figure into the decisions we make in our personal and professional lives. Also, it is not a question we often stop and ask ourselves. From early on, we are placed on an escalator moving up through medical school, residency, fellowship, good job, better job, etc. We are so accustomed to being competitive, to winning, and to wanting to be the best that we sometimes forget to ask ourselves, “What is it exactly that I want, and why? What is my endpoint? And does it make me happy?”

Multitasking is regarded as a talent. As much as we would like to believe that we can do everything at the same time and do it all well, we actually can’t. A friend of mine made me read a book a couple of years ago, called Feeling Good, by David Burns. The book encourages you to consider the different tasks you do in a day and rate how good you are at each of them on a scale of 1 to 10. It then asks you to think about how much enjoyment you derive from each of the tasks and about why you are doing the ones that bring you little to no enjoyment.

I ultimately decided that, for me professionally, the most important thing was my interest in global health. So I decided to do whatever it took to make this happen. But you don’t get something for nothing, and everything comes with sacrifices.

Continue to: Charles Rardin, MD...

Charles Rardin, MD: How exactly did you decide that you were going to focus your career toward pursuing international health? How did you know it was more important? And how did you overcome some of those obstacles?

Dr. Greene: You have to ask the hard question again about what brings you the most joy professionally and personally. That was the easy part of it for me because global health has always been that source of happiness and fulfillment for me. The more challenging parts are the sacrifices and hard choices that come with it. With global health, it can be difficult to balance the demands of a clinical practice.

All of our jobs are a business. I am still struggling with the money part of it. For my husband and I, that meant we had to start small—do what we could afford. But then it blossomed into something that was involving residents, fellows, and med students, which requires far more funding than we had. So I reached out to family. Most of our families donate to different organizations or charities every year, so why not donate to a loved one for something they are passionate about?

At the University of South Florida (USF), we set up a fund, a foundation for global health, which helps support our work abroad as well as the costs associated with involvement of our trainees. Right now, what we have is still small potatoes to a country, but we are making it happen by starting at a small level and growing it.

Beyond the money aspect, traveling abroad means less involvement in meetings, missed opportunities to teach courses that might interest me, and time away from my family. I guess my advice on this whole thing is that you can make things happen if they are important enough to you, and if you are willing to make sacrifices in other areas because you can’t have it all.

Making time for you

Dr. Culligan: So you have found what is important to you, and you have found a way to make it happen. But you are faced with more work; you have given yourself additional work on top of your regular work. How do you make time for a personal life?

Catherine Matthews, MD: In preparing for this discussion, I decided to break down my advice into 3 buckets: The first bucket is discovering and knowing your authentic self. The second is building a community, which I’ll elaborate on. And the third, which we have discussed, is to let go of the money.

Dr. Culligan: I love the concept of the authentic self, but how does that jive with a tendency to strive for perfection? We all think we can do it all. How do we narrow down to what really matters?

Dr. Matthews: We often focus on the things that bring us happiness and what we are good at, but it’s the things that make us unhappy that tend to bring us down. It’s the presence of unhappiness, not the absence of happiness, that seems to be the undoing of many, including myself.

None of us are born with dramatic insight. It is experience that leads to insight. People who are actually present are able to gain insight through observation. A person becomes a better surgeon by observing the outcome of doing a stitch this way versus that; you learn how to do it by seeing what it looks like afterward.

Finding our authentic selves happens in much the same way. Having the presence of mind to ask the right questions, such as, “How am I feeling while I’m doing this?” leads to insights into the true self.

Continue to: It takes a village...

Dr. Greene: Catherine mentioned community earlier, and that is extremely important. The people who surround us can have a huge impact on the way we perceive things, including ourselves. Having a mix of people in our lives—some who practice medicine and others who don’t—helps us stay balanced and answer some of the tough questions. Catherine, for example, has helped me in various stages of my career to ask myself meaningful questions and get real answers.

Dr. Rardin: Part of finding balance is luck, and part of it is making a choice between money and everything else. In considering my first job out of training, I knew that money had the potential to distract me from what was important to me. So I chose a position that was almost entirely salaried so that the decisions I made clinically, surgically, and regarding work-life balance would be less likely to directly impact what was important to me.

Sally Huber, MD: I am still in the “getting there” phase of my life, but one thing I have found is that getting my family involved and excited about what I do has made them much more accepting of when I have longer work days or work to do on the weekend. My spouse has become quite involved with what I have been doing with transgender health in Atlanta. It has been a great bonding experience; she shares my passions, and together we are creating something about which we both can be proud.

When work invades home life

Dr. Culligan: That is great. Sally, I think when we talked, you were just learning about the necessity of mental separation and of not taking your work home with you, which is so hard for all of us with all of our devices.

Dr. Huber: Yes, this year has been about seeing what works best as far as being efficient at work and having quality time at home. At the end of every day I ask myself, “What worked well today? What didn’t work well? What else can I do to maximize time with my family?” I am slowly becoming more efficient, but it has been a challenge. During fellowship, your day is pretty set, but once you are practicing on your own, your hours and responsibilities are completely different, and you have to figure out what works best for you, your values, and your expectations of private life. It takes some time, and I am still figuring it out.

Dr. Culligan: How often would you say that you bring work home? I try hard once I am home to quit working, but sometimes on the weekends I break that rule.

Dr. Matthews: I must say that I do feel like there are certain times when I am better at that than others. Work comes in waves with pressing deadlines. If I averaged it out, probably a third of the time I have some email or some conference call or something that I have got to do at home. I do really try to limit the obligations that I have after 5:30 or 6:00 pm. I resent intrusions after that time. As far as weekends, I delegate about one weekend every 2 months to work, instead of doing a little bit every weekend.

Dr. Greene: I agree. I try hard to make 5:30 to 7:30 pm unequivocal time for a family dinner and time for my kids. During that time, I do not have my phone near me so I can’t look at email or texts. I try not to schedule conference calls. I try to be there to read books to my kids at night. Then if I need to do work, I do it later at night, which interferes with time with my spouse, and is not ideal, but that’s what happens.

Dr. Matthews: One of the things that I think is a huge part of work-life balance is work-related travel. When you are present at work on a consistent basis, the work does not pile up to the extent that it does when you are absent on a trip. When you come back, you invariably pay the price by seeing more patients and doing more surgery. Then it becomes a stressful event.

My advice to young people is to be very thoughtful about planning trips, especially distant ones. You do not want to sit on a plane all day when you could be doing something more productive. If I could have done something differently in my mid-career, I would have traveled less.

Continue to: Prioritizing “out of office” time...

Dr. Greene: How do you all mentally separate yourself from work, so that when you are on vacation with your family you are not thinking about the office, the patients, and all of the things on your to-do list?

Dr. Rardin: I don’t have a great answer for that except that it is about being present. You have to decide that now is the time when I am home, now is the time when I am a parent, now is the time when I am a boy scout leader, etc. I guess maybe it’s a skill, or maybe it’s about making something a priority. Work will always be waiting for you when you turn your attention back to it.

Dr. Matthews: Kristie, the answer to your question goes back to community. Partners in a practice cover for each other. You have to trust them to take care of things so that you can relax during your time away.

Some people recommend not scheduling challenging cases right before going away because invariably something goes wrong, and then you are asking, “Why did I schedule 3 colpopexies before getting on a plane?”

Dr. Rardin: Yes, I completely agree with all of that. Personally, I feel fortunate that I can compartmentalize pretty well. When I am home with my kids, I allow myself to shed some of the doctor/surgeon/leadership persona; I am able to be goofy and completely non–doctor-like. It works to help me leave work behind.

Dr. Matthews: Other things you can do include setting up an out-of-office notice on your email that says when you will be back and what to do in case of urgent matters. This basically says to the world, “Don’t expect to hear from me until X date.” It removes the expectation that you will respond sooner. Otherwise, we would all be on our smartphones all the time and not enjoying our time away.

What I wish I knew then

Dr. Culligan: How would you complete the sentence, “I wish they had told me X when I was embarking on my career?”

Dr. Rardin: I keep coming back to the phrase, “Don’t do anything that you can reasonably pay someone else to do.” By that I mean, if you don’t get energy from housework, consider spending some of your money to get help with the housework. Resolve to make a relatively small expenditure to maximize the quality of the time that you give to yourself and your family. Those are the sorts of things that I think can go a long way.

Dr. Culligan: Charley, your wife is an ObGyn. How do you navigate a dual medical career household? What advice do you have for others?

Dr. Rardin: When I was going into fellowship, we had a conversation about how hard it is for both people in a relationship to have an academic fire in the belly and to be truly engaged in climbing the academic ladder. We made a decision that Jane would go into private practice. There has got to be some give and take in a dual medical relationship; a lot of sacrifices and compromises need to happen. We are fortunate in that there are complementary aspects to our jobs. We both spend about the same number of nights away from the house, but my travel is more in chunks and hers is overnight calls for labor and delivery. We have different ways of (briefly) single-parenting, and you have to come up with ways to handle the domestic chores.

Dr. Matthews: I wish someone had explained to me that the people you work with are much more important than the place. The human connection is what defines your experience, much more than any ego-driven outcome.

Dr. Greene: I wish someone had explained to me the competing aspects of academic medicine. The cards are stacked in a way that make it difficult for you to win. For example, you may love to teach and may be really good at it, but if you let your students handle too many cases, your relative value units plummet and then the hospital is on your back. There are the interests of people, and there are the interests of the business. Everything is a balance, and it’s really tricky.

Dr. Huber: Luckily, Pat counselled me as I was finishing my fellowship about the importance of negotiating a good contract, of being pushy and knowing what you want out of it and knowing what your limitations are. I joined a private practice that had 3 different physical locations. If I had to drive to all of them, as they wanted, it would have meant up to a one-and-a-half-hour commute. But I pushed to stay in one location and to put that extra hour to better use. I am glad I did, but it was terrifying at the time because I didn’t want to lose the offer. I know people that did not do that and took the first thing they got. Now, they are driving all over the place or they have these crazy hours or terrible call responsibilities that if they had just been a little firmer, they probably could have gotten out of. As they start trying to find work-life balance, they are already handicapped.

Continue to: Passions outside the office...

Passions outside the office

Dr. Culligan: One thing I would like to touch on is what is going on in each of your personal lives because all of you have interesting stories to tell outside of what you do professionally. What drives you other than medicine?

Dr. Rardin: I am the father of 3 boys. The oldest one just got his Eagle Scout rank yesterday in Boy Scouts. I would be a woodworker if I wasn’t in medicine. I am a Deacon at church. And I love to spend my downtime reading with my family in front of the fireplace.

Dr. Matthews: For me, it’s music. When my husband and I first met, he asked me if I played a musical instrument. I said I played the cello in primary school. He said, “Great, go rent a cello.” I was never at all interested in playing the cello by myself, but because he plays guitar and piano we became able to play a lot of music together. Our son, Alexander, plays drums. We now have a family band.

In addition, I do yoga. I would never have labeled myself an anxious person, but I learned through this process that I am and need to manage it. It took a lot of years to figure that out. If I don’t leave myself an hour each day to go to a yoga class, I am not a happy person and neither is anyone around me. Also, I get tremendous pleasure from reading books and magazines as opposed to watching a screen.

Dr. Greene: I have found that my passions outside of work often change depending on my stage of life. Right now, I have two young babies and so my life outside of work revolves around them. Before the babies, my dad, who lives in Buffalo, was ill. So for awhile, we were flying to Buffalo almost every weekend that I was not on call. I would say, in general what fuels me is connecting with the people I love as often as I can. A typical night involves me and my husband going for a walk with our kids and dog after dinner and talking to each other. We connect with neighbors and chat on the front porch. It doesn’t really matter what we are doing; it is about being surrounded by people who matter.

Dr. Huber: It’s similar for me. Having a child completely shifts your world view. My goal every day is to give my daughter her first feeding in the morning and to get home as soon as possible at the end of the day to do her last feeding and put her to sleep. She crawled for the first time yesterday, and I was so excited that I could be there for that.

Also, I love being outdoors. I love hiking and camping. Going on a hike and being outside with nature is my way of decompressing.

Continue to: Thinking about upcoming generations...

Dr. Matthews: One other thing I would like to propose is looking at what can we do to make the profession better for the next generation. As a group, our profession is somewhat inflexible. We tend to fall into the trap of, “since this is the way we have always done it this is how we should continue doing it.” The OR still starts at 7:00 or 7:30 am, ignoring the need for school drop-offs, etc. We are not innovative about flexibility in the work week. Honestly, it does not work well for many people, patients and physicians alike. Flexible scheduling should be something that is on the table for both men and women who are trying to balance being full-time parents and full-time surgeons. We need to create an environment in which it is okay for you to spend 10 years instead of 6 as an assistant professor because you are also a young parent, and it will not count against you when you come up for promotion.

Dr. Culligan: I agree with you, Catherine. Full “Professor” is a nice title, but it means time away from family and a lot of other things. Each of us has to decide whether it is worth it, especially since it often does not come with any extra money.

Dr. Huber: A question on a recent survey of residents asked, “Do you see yourself going into private practice or academic medicine when you’ve completed your residency?” When I was a resident, everyone wanted to go into academic medicine, but now it seems like more and more residents have their sights set on private practice because that is where they see the opportunities to create work-life balance.

In the academic world, you have to try to get a promotion in X number of years, and get X number of publications, and be a great teacher, doctor, and administrator all at the same time. I am wondering if we are going to start seeing more and more residents and fellows going into private or hospital-owned practice where there aren’t those added expectations.

Dr. Rardin: I agree, and we are back to what we said in the beginning about doing an honest assessment of what is meaningful and important. We are all trained to try to reach for that shiny brass ring, but do we really want that brass ring? Will it be an asset or a hindrance once we get it? It is okay to be honest and say, “I really don’t want that promotion. I would rather spend more time with my family.” ●

© TRENDOBJECTS/SHUTTERSTOCK

I often say that there are both “guardrail” days and very good days when it comes to the ins and outs of health care builds and product launches. The process is much like starting down the path of a country road in the middle of a blizzard—unless you have dependable wipers and a good defrost system, that path can get murky very quickly. With this article I hope to offer my counsel to inventors, featuring a few of my prior launches as well as case studies of health care launches I was not involved with, and sharing the lessons learned and hurdles that were overcome. I encourage all entrepreneurs to act on their ideas because, in the world of health care startups, the only failure is not acting on an invention.

Case study 1: Cerezyme

Today, Cerezyme is indicated for patients with Gaucher, which is a lysosomal storage disorder. Cerezyme’s first-generation product, called Ceredase, was a human tissue-derived protein that we extracted from human placentas. At the time, the concept of moving this program forward was denied by the Board of Directors because they said that even if you could collect enough placentas to make the enzyme, it would be too expensive to manufacture. In fact, early scale-up modeling for manufacturing the protein demonstrated that Genzyme would need 4 tons of placentas per Gaucher patient per year.

Gaucher is a severe, early-onset disease that has a significant negative outcome for patients. Patients with Gaucher are in dire need of treatment. Genzyme went forward with the Ceredase program by financing it through the families of patients with the disease, by starting an LLC separate from the business and funding the initial clinical trial and the development of the protein through the families of Gaucher patients. That approach was a successful endeavor. A great example of a creative capital structure to advance a program.

This was in the late 1980s/early 1990s, and at the height of the AIDS challenge. Genzyme based the manufacturing in Lille, France, and we cryopreserved placentas in the United States and Europe and shipped them to Lille to be processed into therapy. Genzyme eventually received approval for Ceredase from the US Food and Drug Administration (FDA) and the European Medicines Agency. At the height of the placenta collection, we were gathering about 10% to 15% of the placentas in the United States and 30% to 40% of the placentas in Europe. Resources supply became an issue until we developed a recombinant form of the protein, accomplished by using a manufacturing system called a CHO cell line.

This is a very good success story: If this invention was not pursued, Gaucher patients would not benefit from the treatment today. In addition, there are a plethora of patients with different lysosomal storage disorders treated with additional proteins that have been aided by us going through the entire development, manufacturing, and global commercialization process. We figured out how to manufacture and deliver the treatment, working through multiple countries’ political systems, and today the therapy is paid for by insurance and government systems on a worldwide basis.

Continue to: Case study 2...

Case study 2: ThinPrep

I like to use the approval of ThinPrep as an example of avoiding a false negative—a stoppage in the development of the product or drug for the wrong reasons. False negatives, in my mind, occur when you are developing a technology and you run into issues during the clinical phase and/or with FDA approval, or with a technical failure or you run out of capital prior to knowing whether or not the innovation actually works. In the case of ThinPrep, a poorly run clinical trial almost resulted in a false negative.

The company at the time was Cytyc, and an initial clinical study presented to the FDA yielded a neutral-negative outcome. The FDA said that there were not enough data to show the differentiation from the current Pap smear standard of care.

The founders of the company at that time had inherited the study protocol from a prior leadership team, so they had to finish the trial with the initial protocol. Given the FDA’s advisement, they developed a new trial. It took the persistence of these two founders, who mortgaged their homes and spent their personal dollars to take this through the next wave of clinical development. In the end it was successful. The revised clinical trial yielded an approval for ThinPrep, which is now considered a standard of care.

The use of ThinPrep reduced cervical cancer deaths by 40% from preapproval. The challenging path from clinical development to eventual commercial launch and physician leadership in advancing patient care makes the story of ThinPrep a great example of not allowing an early false negative of a poorly designed and run clinical trial stop important innovation.

Case study 3: Cologuard

The development of Cologuard is a case study demonstrating that, sometimes, when your first attempt does not work, you need to have the persistence to raise additional capital and/or use a slightly different technical approach. The approval story of Cologuard is important to share because it is an important cancer screening diagnostic, using DNA from stool samples to test for colon cancer, giving access to important colon cancer screening to many patients. Currently, caregivers are only scraping the surface with Cologuard’s ability to screen the population. There are many more patients that need access to the test, and I believe they will get it in the years ahead.

Cologuard went through a first- and second-generational technical failure. They could not get the test’s specificity and sensitivity to be at the level of a screening tool; there were too many false-positive results. With the third iteration came the technical breakthrough, and a very large, expensive study was conducted—one the leadership team was criticized for. However, that study yielded the data that achieved a New England Journal of Medicine article, and reimbursement support across the country. The combination of the right technical team and the right leadership team, who planned a proper commercial launch, with a CEO that supported the extensive clinical study, has resulted in the fourth generation of Cologuard—an important breakthrough offering a very useful new standard of care in colon cancer detection and screening.

Continue to: Pearls for moving your innovations forward...

Pearls for moving your innovations forward

Because of my experience in undergoing health care start-ups, and contributing to several of those advancements of innovation, many inventors approach me for advice on their paths from idea to full-concept company. Here are a few of my lessons learned.

Consider purpose, not financial gain, first and foremost. Financial gain is typically the by-product or outcome of a standard-of-care breakthrough for inventors, but it’s a very hard road. Pursue your invention for advancing patient care and moving a new standard of care forward in health care versus financial gain at the end.

Determine whether your invention is a product or a company, or potentially, not capitalizable at all. Figure this out early. Analyze your idea to make sure it is sound and truly novel. Analyze the competition and to make sure it is sound and truly novel. Analyze the competition and the market dynamics to support a new product. Can the development path be defined very clearly to raise capital? Is your innovation a big enough breakthrough in the market with several current products to actually make a difference in patient outcomes (and eventually achieve product reimbursement)? The creation of a company may be the right strategy if the innovation can support a differentiated enough breakthrough where you can actually support all the infrastructure to build the business. If you find that the market is not there to support and develop your idea to eventual success, backing off early is important to preserve invested capital.

Protect early. Is your invention patentable, or has someone else already thought of the idea? What kind of patent(s) are appropriate? Where, geographically, do you want to protect your invention? Find a good patent attorney in your local area, early in the process, to help you answer all of these critical questions. Patents are expensive to file and maintain, but it is not expensive to do a literature search to find out if your idea is novel. A provisional patent, which would be your first step, is an important cost-effective step.

Capital is out there. If your invention or idea deserves capital, it is available. I will address raising capital in more detail in the next section.

Consider regulatory and manufacturing as achievable hurdles. Inventors often get tripped up here, considering the regulatory hurdles and manufacturing too challenging and abandoning their ideas because the risk is too great. Regulatory and manufacturing are very important aspects of health care standard-of-care builds. Cutting corners is not an option. That said, regulatory and manufacturing should not stop you. Challenges often can be worked through as long as the clinical need is there, and the clinical data support bringing that technology forward.

Consider corporate partnerships. I am a fan of corporate partners. But which ones should you target, and when and why? Corporate partnerships can bring significant capital, which is great, but there is enough investor capital out there that you should not pursue a corporate partner just for capital. The main benefit of a corporate partner is enterprise intellect. They typically know more about the field that you are entering than the investors or a small company leadership team.

Establish and listen to advisors. When thinking about who to trust, research their track record. Advisors who have gone through this process before, and specifically in your product area, are important to have access to.

Persistence is key. I have observed a tremendous “compression of innovation” in the health care areas that I have been involved with—human tissue-derived proteins, robotic surgery, stem cell therapy, and digital health (which is still in its infancy). For each of these breakthrough categories, early on, it appeared that it couldn’t be done. However, after the first 2 or 3 major breakthroughs in each one of these areas, a compression of innovation occurred. For instance, after approximately 15 years of protein development, we came out with the recombinant manufacturing systems for proteins. Very quickly, within 10 years, there were more than 70 proteins on the market. The persistence of the inventors to overcome early obstacles in each of these health care areas was critical to future success in each area.

Continue to: Raising capital...

Raising capital

There are different investors who specialize in different types of investment opportunities. The first phase of raising capital is the seed round—where there is typically early data, or even no data and just a concept. From this seed round forward, there is less risk as you develop your technology; thus, there are different investors that support different stages of development and that specialize in different types of investing. It is important to target the right investors and raise enough capital to be able to go achieve multiple operational milestones. Otherwise, when you go through your first round of capital, or the Series A or B financing rounds, there may not be a set of investors out there to fund the company moving forward. Health care investors will make it known that they invest in certain rounds of capital. You can determine who those investors are by doing a search online.

A mistake health care inventors can make is not taking enough capital from investors, because they are concerned about dilution. I advise investors not to focus on dilution but rather on, how big can you make “the pie” (value of the company) worth? The entire process is about bringing a true product through to a new standard-of-care curve.

Trust is the most important thing to earn with investors, and there is zero tolerance for a lack of trust. Share your vision as the inventor with investors, who want to know where this category could be in the next 5 or 10 years. Clinical data will always win, and health care investors and industry leaders should be focused on executing the most robust clinical data to demonstrate the clearest potential clinical outcome. Investors will follow a good plan that has been developed to achieve FDA approval, successful commercialization or “go to market” launch, and eventual reimbursement to support a true standard-of-care change.

Failure is defined by inaction

The 3 case studies that I have shared were success stories because the ideas and inventions were acted upon. When I was at Genzyme, we built the company up to more than $1 billion in revenue. We commercialized proteins in over 50 countries. Most importantly, many patients benefited from the innovation. If you have an invention and an idea, act on it—and surround yourself with great people in every discipline. Having the right people and team is extremely important. ●

© TRENDOBJECTS/SHUTTERSTOCK

I often say that there are both “guardrail” days and very good days when it comes to the ins and outs of health care builds and product launches. The process is much like starting down the path of a country road in the middle of a blizzard—unless you have dependable wipers and a good defrost system, that path can get murky very quickly. With this article I hope to offer my counsel to inventors, featuring a few of my prior launches as well as case studies of health care launches I was not involved with, and sharing the lessons learned and hurdles that were overcome. I encourage all entrepreneurs to act on their ideas because, in the world of health care startups, the only failure is not acting on an invention.

Case study 1: Cerezyme

Today, Cerezyme is indicated for patients with Gaucher, which is a lysosomal storage disorder. Cerezyme’s first-generation product, called Ceredase, was a human tissue-derived protein that we extracted from human placentas. At the time, the concept of moving this program forward was denied by the Board of Directors because they said that even if you could collect enough placentas to make the enzyme, it would be too expensive to manufacture. In fact, early scale-up modeling for manufacturing the protein demonstrated that Genzyme would need 4 tons of placentas per Gaucher patient per year.

Gaucher is a severe, early-onset disease that has a significant negative outcome for patients. Patients with Gaucher are in dire need of treatment. Genzyme went forward with the Ceredase program by financing it through the families of patients with the disease, by starting an LLC separate from the business and funding the initial clinical trial and the development of the protein through the families of Gaucher patients. That approach was a successful endeavor. A great example of a creative capital structure to advance a program.

This was in the late 1980s/early 1990s, and at the height of the AIDS challenge. Genzyme based the manufacturing in Lille, France, and we cryopreserved placentas in the United States and Europe and shipped them to Lille to be processed into therapy. Genzyme eventually received approval for Ceredase from the US Food and Drug Administration (FDA) and the European Medicines Agency. At the height of the placenta collection, we were gathering about 10% to 15% of the placentas in the United States and 30% to 40% of the placentas in Europe. Resources supply became an issue until we developed a recombinant form of the protein, accomplished by using a manufacturing system called a CHO cell line.

This is a very good success story: If this invention was not pursued, Gaucher patients would not benefit from the treatment today. In addition, there are a plethora of patients with different lysosomal storage disorders treated with additional proteins that have been aided by us going through the entire development, manufacturing, and global commercialization process. We figured out how to manufacture and deliver the treatment, working through multiple countries’ political systems, and today the therapy is paid for by insurance and government systems on a worldwide basis.

Continue to: Case study 2...

Case study 2: ThinPrep

I like to use the approval of ThinPrep as an example of avoiding a false negative—a stoppage in the development of the product or drug for the wrong reasons. False negatives, in my mind, occur when you are developing a technology and you run into issues during the clinical phase and/or with FDA approval, or with a technical failure or you run out of capital prior to knowing whether or not the innovation actually works. In the case of ThinPrep, a poorly run clinical trial almost resulted in a false negative.

The company at the time was Cytyc, and an initial clinical study presented to the FDA yielded a neutral-negative outcome. The FDA said that there were not enough data to show the differentiation from the current Pap smear standard of care.

The founders of the company at that time had inherited the study protocol from a prior leadership team, so they had to finish the trial with the initial protocol. Given the FDA’s advisement, they developed a new trial. It took the persistence of these two founders, who mortgaged their homes and spent their personal dollars to take this through the next wave of clinical development. In the end it was successful. The revised clinical trial yielded an approval for ThinPrep, which is now considered a standard of care.

The use of ThinPrep reduced cervical cancer deaths by 40% from preapproval. The challenging path from clinical development to eventual commercial launch and physician leadership in advancing patient care makes the story of ThinPrep a great example of not allowing an early false negative of a poorly designed and run clinical trial stop important innovation.

Case study 3: Cologuard

The development of Cologuard is a case study demonstrating that, sometimes, when your first attempt does not work, you need to have the persistence to raise additional capital and/or use a slightly different technical approach. The approval story of Cologuard is important to share because it is an important cancer screening diagnostic, using DNA from stool samples to test for colon cancer, giving access to important colon cancer screening to many patients. Currently, caregivers are only scraping the surface with Cologuard’s ability to screen the population. There are many more patients that need access to the test, and I believe they will get it in the years ahead.

Cologuard went through a first- and second-generational technical failure. They could not get the test’s specificity and sensitivity to be at the level of a screening tool; there were too many false-positive results. With the third iteration came the technical breakthrough, and a very large, expensive study was conducted—one the leadership team was criticized for. However, that study yielded the data that achieved a New England Journal of Medicine article, and reimbursement support across the country. The combination of the right technical team and the right leadership team, who planned a proper commercial launch, with a CEO that supported the extensive clinical study, has resulted in the fourth generation of Cologuard—an important breakthrough offering a very useful new standard of care in colon cancer detection and screening.

Continue to: Pearls for moving your innovations forward...

Pearls for moving your innovations forward

Because of my experience in undergoing health care start-ups, and contributing to several of those advancements of innovation, many inventors approach me for advice on their paths from idea to full-concept company. Here are a few of my lessons learned.

Consider purpose, not financial gain, first and foremost. Financial gain is typically the by-product or outcome of a standard-of-care breakthrough for inventors, but it’s a very hard road. Pursue your invention for advancing patient care and moving a new standard of care forward in health care versus financial gain at the end.

Determine whether your invention is a product or a company, or potentially, not capitalizable at all. Figure this out early. Analyze your idea to make sure it is sound and truly novel. Analyze the competition and to make sure it is sound and truly novel. Analyze the competition and the market dynamics to support a new product. Can the development path be defined very clearly to raise capital? Is your innovation a big enough breakthrough in the market with several current products to actually make a difference in patient outcomes (and eventually achieve product reimbursement)? The creation of a company may be the right strategy if the innovation can support a differentiated enough breakthrough where you can actually support all the infrastructure to build the business. If you find that the market is not there to support and develop your idea to eventual success, backing off early is important to preserve invested capital.

Protect early. Is your invention patentable, or has someone else already thought of the idea? What kind of patent(s) are appropriate? Where, geographically, do you want to protect your invention? Find a good patent attorney in your local area, early in the process, to help you answer all of these critical questions. Patents are expensive to file and maintain, but it is not expensive to do a literature search to find out if your idea is novel. A provisional patent, which would be your first step, is an important cost-effective step.

Capital is out there. If your invention or idea deserves capital, it is available. I will address raising capital in more detail in the next section.

Consider regulatory and manufacturing as achievable hurdles. Inventors often get tripped up here, considering the regulatory hurdles and manufacturing too challenging and abandoning their ideas because the risk is too great. Regulatory and manufacturing are very important aspects of health care standard-of-care builds. Cutting corners is not an option. That said, regulatory and manufacturing should not stop you. Challenges often can be worked through as long as the clinical need is there, and the clinical data support bringing that technology forward.

Consider corporate partnerships. I am a fan of corporate partners. But which ones should you target, and when and why? Corporate partnerships can bring significant capital, which is great, but there is enough investor capital out there that you should not pursue a corporate partner just for capital. The main benefit of a corporate partner is enterprise intellect. They typically know more about the field that you are entering than the investors or a small company leadership team.

Establish and listen to advisors. When thinking about who to trust, research their track record. Advisors who have gone through this process before, and specifically in your product area, are important to have access to.

Persistence is key. I have observed a tremendous “compression of innovation” in the health care areas that I have been involved with—human tissue-derived proteins, robotic surgery, stem cell therapy, and digital health (which is still in its infancy). For each of these breakthrough categories, early on, it appeared that it couldn’t be done. However, after the first 2 or 3 major breakthroughs in each one of these areas, a compression of innovation occurred. For instance, after approximately 15 years of protein development, we came out with the recombinant manufacturing systems for proteins. Very quickly, within 10 years, there were more than 70 proteins on the market. The persistence of the inventors to overcome early obstacles in each of these health care areas was critical to future success in each area.

Continue to: Raising capital...

Raising capital

There are different investors who specialize in different types of investment opportunities. The first phase of raising capital is the seed round—where there is typically early data, or even no data and just a concept. From this seed round forward, there is less risk as you develop your technology; thus, there are different investors that support different stages of development and that specialize in different types of investing. It is important to target the right investors and raise enough capital to be able to go achieve multiple operational milestones. Otherwise, when you go through your first round of capital, or the Series A or B financing rounds, there may not be a set of investors out there to fund the company moving forward. Health care investors will make it known that they invest in certain rounds of capital. You can determine who those investors are by doing a search online.

A mistake health care inventors can make is not taking enough capital from investors, because they are concerned about dilution. I advise investors not to focus on dilution but rather on, how big can you make “the pie” (value of the company) worth? The entire process is about bringing a true product through to a new standard-of-care curve.

Trust is the most important thing to earn with investors, and there is zero tolerance for a lack of trust. Share your vision as the inventor with investors, who want to know where this category could be in the next 5 or 10 years. Clinical data will always win, and health care investors and industry leaders should be focused on executing the most robust clinical data to demonstrate the clearest potential clinical outcome. Investors will follow a good plan that has been developed to achieve FDA approval, successful commercialization or “go to market” launch, and eventual reimbursement to support a true standard-of-care change.

Failure is defined by inaction

The 3 case studies that I have shared were success stories because the ideas and inventions were acted upon. When I was at Genzyme, we built the company up to more than $1 billion in revenue. We commercialized proteins in over 50 countries. Most importantly, many patients benefited from the innovation. If you have an invention and an idea, act on it—and surround yourself with great people in every discipline. Having the right people and team is extremely important. ●

© TRENDOBJECTS/SHUTTERSTOCK

I often say that there are both “guardrail” days and very good days when it comes to the ins and outs of health care builds and product launches. The process is much like starting down the path of a country road in the middle of a blizzard—unless you have dependable wipers and a good defrost system, that path can get murky very quickly. With this article I hope to offer my counsel to inventors, featuring a few of my prior launches as well as case studies of health care launches I was not involved with, and sharing the lessons learned and hurdles that were overcome. I encourage all entrepreneurs to act on their ideas because, in the world of health care startups, the only failure is not acting on an invention.

Case study 1: Cerezyme

Today, Cerezyme is indicated for patients with Gaucher, which is a lysosomal storage disorder. Cerezyme’s first-generation product, called Ceredase, was a human tissue-derived protein that we extracted from human placentas. At the time, the concept of moving this program forward was denied by the Board of Directors because they said that even if you could collect enough placentas to make the enzyme, it would be too expensive to manufacture. In fact, early scale-up modeling for manufacturing the protein demonstrated that Genzyme would need 4 tons of placentas per Gaucher patient per year.

Gaucher is a severe, early-onset disease that has a significant negative outcome for patients. Patients with Gaucher are in dire need of treatment. Genzyme went forward with the Ceredase program by financing it through the families of patients with the disease, by starting an LLC separate from the business and funding the initial clinical trial and the development of the protein through the families of Gaucher patients. That approach was a successful endeavor. A great example of a creative capital structure to advance a program.

This was in the late 1980s/early 1990s, and at the height of the AIDS challenge. Genzyme based the manufacturing in Lille, France, and we cryopreserved placentas in the United States and Europe and shipped them to Lille to be processed into therapy. Genzyme eventually received approval for Ceredase from the US Food and Drug Administration (FDA) and the European Medicines Agency. At the height of the placenta collection, we were gathering about 10% to 15% of the placentas in the United States and 30% to 40% of the placentas in Europe. Resources supply became an issue until we developed a recombinant form of the protein, accomplished by using a manufacturing system called a CHO cell line.

This is a very good success story: If this invention was not pursued, Gaucher patients would not benefit from the treatment today. In addition, there are a plethora of patients with different lysosomal storage disorders treated with additional proteins that have been aided by us going through the entire development, manufacturing, and global commercialization process. We figured out how to manufacture and deliver the treatment, working through multiple countries’ political systems, and today the therapy is paid for by insurance and government systems on a worldwide basis.

Continue to: Case study 2...

Case study 2: ThinPrep

I like to use the approval of ThinPrep as an example of avoiding a false negative—a stoppage in the development of the product or drug for the wrong reasons. False negatives, in my mind, occur when you are developing a technology and you run into issues during the clinical phase and/or with FDA approval, or with a technical failure or you run out of capital prior to knowing whether or not the innovation actually works. In the case of ThinPrep, a poorly run clinical trial almost resulted in a false negative.

The company at the time was Cytyc, and an initial clinical study presented to the FDA yielded a neutral-negative outcome. The FDA said that there were not enough data to show the differentiation from the current Pap smear standard of care.

The founders of the company at that time had inherited the study protocol from a prior leadership team, so they had to finish the trial with the initial protocol. Given the FDA’s advisement, they developed a new trial. It took the persistence of these two founders, who mortgaged their homes and spent their personal dollars to take this through the next wave of clinical development. In the end it was successful. The revised clinical trial yielded an approval for ThinPrep, which is now considered a standard of care.

The use of ThinPrep reduced cervical cancer deaths by 40% from preapproval. The challenging path from clinical development to eventual commercial launch and physician leadership in advancing patient care makes the story of ThinPrep a great example of not allowing an early false negative of a poorly designed and run clinical trial stop important innovation.

Case study 3: Cologuard

The development of Cologuard is a case study demonstrating that, sometimes, when your first attempt does not work, you need to have the persistence to raise additional capital and/or use a slightly different technical approach. The approval story of Cologuard is important to share because it is an important cancer screening diagnostic, using DNA from stool samples to test for colon cancer, giving access to important colon cancer screening to many patients. Currently, caregivers are only scraping the surface with Cologuard’s ability to screen the population. There are many more patients that need access to the test, and I believe they will get it in the years ahead.

Cologuard went through a first- and second-generational technical failure. They could not get the test’s specificity and sensitivity to be at the level of a screening tool; there were too many false-positive results. With the third iteration came the technical breakthrough, and a very large, expensive study was conducted—one the leadership team was criticized for. However, that study yielded the data that achieved a New England Journal of Medicine article, and reimbursement support across the country. The combination of the right technical team and the right leadership team, who planned a proper commercial launch, with a CEO that supported the extensive clinical study, has resulted in the fourth generation of Cologuard—an important breakthrough offering a very useful new standard of care in colon cancer detection and screening.

Continue to: Pearls for moving your innovations forward...

Pearls for moving your innovations forward

Because of my experience in undergoing health care start-ups, and contributing to several of those advancements of innovation, many inventors approach me for advice on their paths from idea to full-concept company. Here are a few of my lessons learned.

Consider purpose, not financial gain, first and foremost. Financial gain is typically the by-product or outcome of a standard-of-care breakthrough for inventors, but it’s a very hard road. Pursue your invention for advancing patient care and moving a new standard of care forward in health care versus financial gain at the end.

Determine whether your invention is a product or a company, or potentially, not capitalizable at all. Figure this out early. Analyze your idea to make sure it is sound and truly novel. Analyze the competition and to make sure it is sound and truly novel. Analyze the competition and the market dynamics to support a new product. Can the development path be defined very clearly to raise capital? Is your innovation a big enough breakthrough in the market with several current products to actually make a difference in patient outcomes (and eventually achieve product reimbursement)? The creation of a company may be the right strategy if the innovation can support a differentiated enough breakthrough where you can actually support all the infrastructure to build the business. If you find that the market is not there to support and develop your idea to eventual success, backing off early is important to preserve invested capital.

Protect early. Is your invention patentable, or has someone else already thought of the idea? What kind of patent(s) are appropriate? Where, geographically, do you want to protect your invention? Find a good patent attorney in your local area, early in the process, to help you answer all of these critical questions. Patents are expensive to file and maintain, but it is not expensive to do a literature search to find out if your idea is novel. A provisional patent, which would be your first step, is an important cost-effective step.

Capital is out there. If your invention or idea deserves capital, it is available. I will address raising capital in more detail in the next section.

Consider regulatory and manufacturing as achievable hurdles. Inventors often get tripped up here, considering the regulatory hurdles and manufacturing too challenging and abandoning their ideas because the risk is too great. Regulatory and manufacturing are very important aspects of health care standard-of-care builds. Cutting corners is not an option. That said, regulatory and manufacturing should not stop you. Challenges often can be worked through as long as the clinical need is there, and the clinical data support bringing that technology forward.

Consider corporate partnerships. I am a fan of corporate partners. But which ones should you target, and when and why? Corporate partnerships can bring significant capital, which is great, but there is enough investor capital out there that you should not pursue a corporate partner just for capital. The main benefit of a corporate partner is enterprise intellect. They typically know more about the field that you are entering than the investors or a small company leadership team.

Establish and listen to advisors. When thinking about who to trust, research their track record. Advisors who have gone through this process before, and specifically in your product area, are important to have access to.

Persistence is key. I have observed a tremendous “compression of innovation” in the health care areas that I have been involved with—human tissue-derived proteins, robotic surgery, stem cell therapy, and digital health (which is still in its infancy). For each of these breakthrough categories, early on, it appeared that it couldn’t be done. However, after the first 2 or 3 major breakthroughs in each one of these areas, a compression of innovation occurred. For instance, after approximately 15 years of protein development, we came out with the recombinant manufacturing systems for proteins. Very quickly, within 10 years, there were more than 70 proteins on the market. The persistence of the inventors to overcome early obstacles in each of these health care areas was critical to future success in each area.

Continue to: Raising capital...

Raising capital

There are different investors who specialize in different types of investment opportunities. The first phase of raising capital is the seed round—where there is typically early data, or even no data and just a concept. From this seed round forward, there is less risk as you develop your technology; thus, there are different investors that support different stages of development and that specialize in different types of investing. It is important to target the right investors and raise enough capital to be able to go achieve multiple operational milestones. Otherwise, when you go through your first round of capital, or the Series A or B financing rounds, there may not be a set of investors out there to fund the company moving forward. Health care investors will make it known that they invest in certain rounds of capital. You can determine who those investors are by doing a search online.

A mistake health care inventors can make is not taking enough capital from investors, because they are concerned about dilution. I advise investors not to focus on dilution but rather on, how big can you make “the pie” (value of the company) worth? The entire process is about bringing a true product through to a new standard-of-care curve.

Trust is the most important thing to earn with investors, and there is zero tolerance for a lack of trust. Share your vision as the inventor with investors, who want to know where this category could be in the next 5 or 10 years. Clinical data will always win, and health care investors and industry leaders should be focused on executing the most robust clinical data to demonstrate the clearest potential clinical outcome. Investors will follow a good plan that has been developed to achieve FDA approval, successful commercialization or “go to market” launch, and eventual reimbursement to support a true standard-of-care change.

Failure is defined by inaction

The 3 case studies that I have shared were success stories because the ideas and inventions were acted upon. When I was at Genzyme, we built the company up to more than $1 billion in revenue. We commercialized proteins in over 50 countries. Most importantly, many patients benefited from the innovation. If you have an invention and an idea, act on it—and surround yourself with great people in every discipline. Having the right people and team is extremely important. ●

If your ObGyn practices are anything like ours, every time there is news coverage of a study regarding mammography or about efforts to pass a breast density inform law, your phone rings with patient calls. In fact, every density inform law enacted in the United States, except for in Illinois, directs patients to their referring provider—generally their ObGyn—to discuss the screening and risk implications of dense breast tissue.

The steady increased awareness of breast density means that we, as ObGyns and other primary care providers (PCPs), have additional responsibilities in managing the breast health of our patients. This includes guiding discussions with patients about what breast density means and whether supplemental screening beyond mammography might be beneficial.

As members of the Medical Advisory Board for DenseBreast-info.org (an online educational resource dedicated to providing breast density information to patients and health care professionals), we are aware of the growing body of evidence demonstrating improved detection of early breast cancer using supplemental screening in dense breasts. However, we know that there is confusion among clinicians about how and when to facilitate tailored screening for women with dense breasts or other breast cancer risk factors. Here we answer 6 questions focusing on how to navigate patient discussions around the topic and the best way to collaborate with radiologists to improve breast care for patients.

Play an active role

1. What role should ObGyns and PCPs play in women’s breast health?

Elizabeth Etkin-Kramer, MD: I am a firm believer that ObGyns and all women’s health providers should be able to assess their patients’ risk of breast cancer and explain the process for managing this risk with their patients. This explanation includes the clinical implications of breast density and when supplemental screening should be employed. It is also important for providers to know when to offer genetic testing and when a patient’s personal or family history indicates supplemental screening with breast magnetic resonance imaging (MRI).

DaCarla M. Albright, MD: I absolutely agree that PCPs, ObGyns, and family practitioners should spend the time to be educated about breast density and supplemental screening options. While the exact role providers play in managing patients’ breast health may vary depending on the practice type or location, the need for knowledge and comfort when talking with patients to help them make informed decisions is critical. Breast health and screening, including the importance of breast density, happen to be a particular interest of mine. I have participated in educational webinars, invited lectures, and breast cancer awareness media events on this topic in the past.

Continue to: Join forces with imaging centers...

Join forces with imaging centers

2. How can ObGyns and radiologists collaborate most effectively to use screening results to personalize breast care for patients?

Dr. Etkin-Kramer: It is important to have a close relationship with the radiologists that read our patients’ mammograms. We need to be able to easily contact the radiologist and quickly get clarification on a patient’s report or discuss next steps. Imaging centers should consider running outreach programs to educate their referring providers on how to risk assess, with this assessment inclusive of breast density. Dinner lectures or grand round meetings are effective to facilitate communication between the radiology community and the ObGyn community. Finally, as we all know, supplemental screening is often subject to copays and deductibles per insurance coverage. If advocacy groups, who are working to eliminate these types of costs, cannot get insurers to waive these payments, we need a less expensive self-pay option.

Dr. Albright: I definitely have and encourage an open line of communication between my practice and breast radiology, as well as our breast surgeons and cancer center to set up consultations as needed. We also invite our radiologists as guests to monthly practice meetings or grand rounds within our department to further improve access and open communication, as this environment is one in which greater provider education on density and adjunctive screening can be achieved.

Know when to refer a high-risk patient

3. Most ObGyns routinely collect family history and perform formal risk assessment. What do you need to know about referring patients to a high-risk program?

Dr. Etkin-Kramer: It is important as ObGyns to be knowledgeable about breast and ovarian cancer risk assessment and genetic testing for cancer susceptibility genes. Our patients expect that of us. I am comfortable doing risk assessment in my office, but I sometimes refer to other specialists in the community if the patient needs additional counseling. For risk assessment, I look at family and personal history, breast density, and other factors that might lead me to believe the patient might carry a hereditary cancer susceptibility gene, including Ashkenazi Jewish ancestry.¹ When indicated, I check lifetime as well as short-term (5- to 10-year) risk, usually using Breast Cancer Surveillance Consortium (BCSC) or Tyrer-Cuzick/International Breast Cancer Intervention Study (IBIS) models, as these include breast density.

I discuss risk-reducing medications. The US Preventive Services Task Force recommends these agents if my patient’s 5-year risk of breast cancer is 1.67% or greater, and I strongly recommend chemoprevention when the patient’s 5-year BCSC risk exceeds 3%, provided likely benefits exceed risks.^2,3 I discuss adding screening breast MRI if lifetime risk by Tyrer-Cuzick exceeds 20%. (Note that Gail and BCSC models are not recommended to be used to determine risk for purposes of supplemental screening with MRI as they do not consider paternal family history nor age of relatives at diagnosis.)

Dr. Albright: ObGyns should be able to ascertain a pertinent history and identify patients at risk for breast cancer based on their personal history, family history, and breast imaging/biopsy history, if relevant. We also need to improve our discussions of supplemental screening for patients who have heterogeneously dense or extremely dense breast tissue. I sense that some ObGyns may rely heavily on the radiologist to suggest supplemental screening, but patients actually look to Ob­Gyns as their providers to have this knowledge and give them direction.

Since I practice at a large academic medical center, I have the opportunity to refer patients to our Breast Cancer Genetics Program because I may be limited on time for counseling in the office and do not want to miss salient details. With all of the information I have ascertained about the patient, I am able to determine and encourage appropriate screening and assure insurance coverage for adjunctive breast MRI when appropriate.

Continue to: Consider how you order patients’ screening to reduce barriers and cost...

4. How would you suggest reducing barriers when referring patients for supplemental screening, such as MRI for high-risk women or ultrasound for those with dense breasts? Would you prefer it if such screening could be performed without additional script/referral? How does insurance coverage factor in?

Dr. Etkin-Kramer: I would love for a screening mammogram with possible ultrasound, on one script, to be the norm. One of the centers that I work with accepts a script written this way. Further, when a patient receives screening at a freestanding facility as opposed to a hospital, the fee for the supplemental screening may be lower because they do not add on a facility fee.

Dr. Albright: We have an order in our electronic health record that allows for screening mammography but adds on diagnostic mammography/bilateral ultrasonography, if indicated by imaging. I am mostly ordering that option now for all of my screening patients; rarely have I had issues with insurance accepting that script. As for when ordering an MRI, I always try to ensure that I have done the patient’s personal risk assessment and included that lifetime breast cancer risk on the order. If the risk is 20% or higher, I typically do not have any insurance coverage issues. If I am ordering MRI as supplemental screening, I typically order the “Fast MRI” protocol that our center offers. This order incurs a $299 out-of-pocket cost for the patient. Any patient with heterogeneously or extremely dense breasts on mammography should have this option, but it requires patient education, discussion with the provider, and an additional cost. I definitely think that insurers need to consider covering supplemental screening, since breast density is reportable in a majority of the US states and will soon be the national standard.

Pearls for guiding patients

5. How do you discuss breast density and the need for supplemental screening with your patients?

Dr. Etkin-Kramer: I strongly feel that my patients need to know when a screening test has limited ability to do its job. This is the case with dense breasts. Visuals help; when discussing breast density, I like the images supplied by DenseBreast-info.org (FIGURE). I explain the two implications of dense tissue:

• First, dense tissue makes it harder to visualize cancers in the breast—the denser the breasts, the less likely the radiologist can pick up a cancer, so mammographic sensitivity for extremely dense breasts can be as low as 25% to 50%.
• Second, high breast density adds to the risk of developing breast cancer. I explain that supplemental screening will pick up additional cancers in women with dense breasts. For example, breast ultrasound will pick up about 2-3/1000 additional breast cancers per year and MRI or molecular breast imaging (MBI) will pick up much more, perhaps 10/1000.

MRI is more invasive than an ultrasound and uses gadolinium, and MBI has more radiation. Supplemental screening is not endorsed by ACOG’s most recent Committee Opinion from 2017; ⁴ however, patients may choose to have it done. This is where shared-decision making is important.

I strongly recommend that all women’s health care providers complete the CME course on the DenseBreast-info.org website. “ Breast Density: Why It Matters ” is a certified educational program for referring physicians that helps health care professionals learn about breast density, its associated risks, and how best to guide patients regarding breast cancer screening.

Continue to: Dr. Albright...

Dr. Albright: When I discuss breast density, I make sure that patients understand that their mammogram determines the density of their breast tissue. I review that in the higher density categories (heterogeneously dense or extremely dense), there is a higher risk of missing cancer, and that these categories are also associated with a higher risk of breast cancer. I also discuss the potential need for supplemental screening, for which my institution primarily offers Fast MRI. However, we can offer breast ultrasonography instead as an option, especially for those concerned about gadolinium exposure. Our center offers either of these supplemental screenings at a cost of $299. I also review the lack of coverage for supplemental screening by some insurance carriers, as both providers and patients may need to advocate for insurer coverage of adjunct studies.

Educational resources

6. What reference materials, illustrations, or other tools do you use to educate your patients?

Dr. Etkin-Kramer: I frequently use handouts printed from the DenseBreast-info.org website, and there is now a brand new patient fact sheet that I have just started using. I also have an example of breast density categories from fatty replaced to extremely dense on my computer, and I am putting it on a new smart board.

Dr. Albright: The extensive resources available at DenseBreast-info.org can improve both patient and provider knowledge of these important issues, so I suggest patients visit that website, and I use many of the images and visuals to help explain breast density. I even use the materials from the website for educating my resident trainees on breast health and screening. ●

If your ObGyn practices are anything like ours, every time there is news coverage of a study regarding mammography or about efforts to pass a breast density inform law, your phone rings with patient calls. In fact, every density inform law enacted in the United States, except for in Illinois, directs patients to their referring provider—generally their ObGyn—to discuss the screening and risk implications of dense breast tissue.

The steady increased awareness of breast density means that we, as ObGyns and other primary care providers (PCPs), have additional responsibilities in managing the breast health of our patients. This includes guiding discussions with patients about what breast density means and whether supplemental screening beyond mammography might be beneficial.

As members of the Medical Advisory Board for DenseBreast-info.org (an online educational resource dedicated to providing breast density information to patients and health care professionals), we are aware of the growing body of evidence demonstrating improved detection of early breast cancer using supplemental screening in dense breasts. However, we know that there is confusion among clinicians about how and when to facilitate tailored screening for women with dense breasts or other breast cancer risk factors. Here we answer 6 questions focusing on how to navigate patient discussions around the topic and the best way to collaborate with radiologists to improve breast care for patients.

Play an active role

1. What role should ObGyns and PCPs play in women’s breast health?

Elizabeth Etkin-Kramer, MD: I am a firm believer that ObGyns and all women’s health providers should be able to assess their patients’ risk of breast cancer and explain the process for managing this risk with their patients. This explanation includes the clinical implications of breast density and when supplemental screening should be employed. It is also important for providers to know when to offer genetic testing and when a patient’s personal or family history indicates supplemental screening with breast magnetic resonance imaging (MRI).

DaCarla M. Albright, MD: I absolutely agree that PCPs, ObGyns, and family practitioners should spend the time to be educated about breast density and supplemental screening options. While the exact role providers play in managing patients’ breast health may vary depending on the practice type or location, the need for knowledge and comfort when talking with patients to help them make informed decisions is critical. Breast health and screening, including the importance of breast density, happen to be a particular interest of mine. I have participated in educational webinars, invited lectures, and breast cancer awareness media events on this topic in the past.

Continue to: Join forces with imaging centers...

Join forces with imaging centers

2. How can ObGyns and radiologists collaborate most effectively to use screening results to personalize breast care for patients?

Dr. Etkin-Kramer: It is important to have a close relationship with the radiologists that read our patients’ mammograms. We need to be able to easily contact the radiologist and quickly get clarification on a patient’s report or discuss next steps. Imaging centers should consider running outreach programs to educate their referring providers on how to risk assess, with this assessment inclusive of breast density. Dinner lectures or grand round meetings are effective to facilitate communication between the radiology community and the ObGyn community. Finally, as we all know, supplemental screening is often subject to copays and deductibles per insurance coverage. If advocacy groups, who are working to eliminate these types of costs, cannot get insurers to waive these payments, we need a less expensive self-pay option.

Dr. Albright: I definitely have and encourage an open line of communication between my practice and breast radiology, as well as our breast surgeons and cancer center to set up consultations as needed. We also invite our radiologists as guests to monthly practice meetings or grand rounds within our department to further improve access and open communication, as this environment is one in which greater provider education on density and adjunctive screening can be achieved.

Know when to refer a high-risk patient

3. Most ObGyns routinely collect family history and perform formal risk assessment. What do you need to know about referring patients to a high-risk program?

Dr. Etkin-Kramer: It is important as ObGyns to be knowledgeable about breast and ovarian cancer risk assessment and genetic testing for cancer susceptibility genes. Our patients expect that of us. I am comfortable doing risk assessment in my office, but I sometimes refer to other specialists in the community if the patient needs additional counseling. For risk assessment, I look at family and personal history, breast density, and other factors that might lead me to believe the patient might carry a hereditary cancer susceptibility gene, including Ashkenazi Jewish ancestry.¹ When indicated, I check lifetime as well as short-term (5- to 10-year) risk, usually using Breast Cancer Surveillance Consortium (BCSC) or Tyrer-Cuzick/International Breast Cancer Intervention Study (IBIS) models, as these include breast density.

I discuss risk-reducing medications. The US Preventive Services Task Force recommends these agents if my patient’s 5-year risk of breast cancer is 1.67% or greater, and I strongly recommend chemoprevention when the patient’s 5-year BCSC risk exceeds 3%, provided likely benefits exceed risks.^2,3 I discuss adding screening breast MRI if lifetime risk by Tyrer-Cuzick exceeds 20%. (Note that Gail and BCSC models are not recommended to be used to determine risk for purposes of supplemental screening with MRI as they do not consider paternal family history nor age of relatives at diagnosis.)

Dr. Albright: ObGyns should be able to ascertain a pertinent history and identify patients at risk for breast cancer based on their personal history, family history, and breast imaging/biopsy history, if relevant. We also need to improve our discussions of supplemental screening for patients who have heterogeneously dense or extremely dense breast tissue. I sense that some ObGyns may rely heavily on the radiologist to suggest supplemental screening, but patients actually look to Ob­Gyns as their providers to have this knowledge and give them direction.

Since I practice at a large academic medical center, I have the opportunity to refer patients to our Breast Cancer Genetics Program because I may be limited on time for counseling in the office and do not want to miss salient details. With all of the information I have ascertained about the patient, I am able to determine and encourage appropriate screening and assure insurance coverage for adjunctive breast MRI when appropriate.

Continue to: Consider how you order patients’ screening to reduce barriers and cost...

4. How would you suggest reducing barriers when referring patients for supplemental screening, such as MRI for high-risk women or ultrasound for those with dense breasts? Would you prefer it if such screening could be performed without additional script/referral? How does insurance coverage factor in?

Dr. Etkin-Kramer: I would love for a screening mammogram with possible ultrasound, on one script, to be the norm. One of the centers that I work with accepts a script written this way. Further, when a patient receives screening at a freestanding facility as opposed to a hospital, the fee for the supplemental screening may be lower because they do not add on a facility fee.

Dr. Albright: We have an order in our electronic health record that allows for screening mammography but adds on diagnostic mammography/bilateral ultrasonography, if indicated by imaging. I am mostly ordering that option now for all of my screening patients; rarely have I had issues with insurance accepting that script. As for when ordering an MRI, I always try to ensure that I have done the patient’s personal risk assessment and included that lifetime breast cancer risk on the order. If the risk is 20% or higher, I typically do not have any insurance coverage issues. If I am ordering MRI as supplemental screening, I typically order the “Fast MRI” protocol that our center offers. This order incurs a $299 out-of-pocket cost for the patient. Any patient with heterogeneously or extremely dense breasts on mammography should have this option, but it requires patient education, discussion with the provider, and an additional cost. I definitely think that insurers need to consider covering supplemental screening, since breast density is reportable in a majority of the US states and will soon be the national standard.

Pearls for guiding patients

5. How do you discuss breast density and the need for supplemental screening with your patients?

Dr. Etkin-Kramer: I strongly feel that my patients need to know when a screening test has limited ability to do its job. This is the case with dense breasts. Visuals help; when discussing breast density, I like the images supplied by DenseBreast-info.org (FIGURE). I explain the two implications of dense tissue:

• First, dense tissue makes it harder to visualize cancers in the breast—the denser the breasts, the less likely the radiologist can pick up a cancer, so mammographic sensitivity for extremely dense breasts can be as low as 25% to 50%.
• Second, high breast density adds to the risk of developing breast cancer. I explain that supplemental screening will pick up additional cancers in women with dense breasts. For example, breast ultrasound will pick up about 2-3/1000 additional breast cancers per year and MRI or molecular breast imaging (MBI) will pick up much more, perhaps 10/1000.

MRI is more invasive than an ultrasound and uses gadolinium, and MBI has more radiation. Supplemental screening is not endorsed by ACOG’s most recent Committee Opinion from 2017; ⁴ however, patients may choose to have it done. This is where shared-decision making is important.

I strongly recommend that all women’s health care providers complete the CME course on the DenseBreast-info.org website. “ Breast Density: Why It Matters ” is a certified educational program for referring physicians that helps health care professionals learn about breast density, its associated risks, and how best to guide patients regarding breast cancer screening.

Continue to: Dr. Albright...

Dr. Albright: When I discuss breast density, I make sure that patients understand that their mammogram determines the density of their breast tissue. I review that in the higher density categories (heterogeneously dense or extremely dense), there is a higher risk of missing cancer, and that these categories are also associated with a higher risk of breast cancer. I also discuss the potential need for supplemental screening, for which my institution primarily offers Fast MRI. However, we can offer breast ultrasonography instead as an option, especially for those concerned about gadolinium exposure. Our center offers either of these supplemental screenings at a cost of $299. I also review the lack of coverage for supplemental screening by some insurance carriers, as both providers and patients may need to advocate for insurer coverage of adjunct studies.

Educational resources

6. What reference materials, illustrations, or other tools do you use to educate your patients?

Dr. Etkin-Kramer: I frequently use handouts printed from the DenseBreast-info.org website, and there is now a brand new patient fact sheet that I have just started using. I also have an example of breast density categories from fatty replaced to extremely dense on my computer, and I am putting it on a new smart board.

Dr. Albright: The extensive resources available at DenseBreast-info.org can improve both patient and provider knowledge of these important issues, so I suggest patients visit that website, and I use many of the images and visuals to help explain breast density. I even use the materials from the website for educating my resident trainees on breast health and screening. ●

If your ObGyn practices are anything like ours, every time there is news coverage of a study regarding mammography or about efforts to pass a breast density inform law, your phone rings with patient calls. In fact, every density inform law enacted in the United States, except for in Illinois, directs patients to their referring provider—generally their ObGyn—to discuss the screening and risk implications of dense breast tissue.

The steady increased awareness of breast density means that we, as ObGyns and other primary care providers (PCPs), have additional responsibilities in managing the breast health of our patients. This includes guiding discussions with patients about what breast density means and whether supplemental screening beyond mammography might be beneficial.

As members of the Medical Advisory Board for DenseBreast-info.org (an online educational resource dedicated to providing breast density information to patients and health care professionals), we are aware of the growing body of evidence demonstrating improved detection of early breast cancer using supplemental screening in dense breasts. However, we know that there is confusion among clinicians about how and when to facilitate tailored screening for women with dense breasts or other breast cancer risk factors. Here we answer 6 questions focusing on how to navigate patient discussions around the topic and the best way to collaborate with radiologists to improve breast care for patients.

Play an active role

1. What role should ObGyns and PCPs play in women’s breast health?

Elizabeth Etkin-Kramer, MD: I am a firm believer that ObGyns and all women’s health providers should be able to assess their patients’ risk of breast cancer and explain the process for managing this risk with their patients. This explanation includes the clinical implications of breast density and when supplemental screening should be employed. It is also important for providers to know when to offer genetic testing and when a patient’s personal or family history indicates supplemental screening with breast magnetic resonance imaging (MRI).

DaCarla M. Albright, MD: I absolutely agree that PCPs, ObGyns, and family practitioners should spend the time to be educated about breast density and supplemental screening options. While the exact role providers play in managing patients’ breast health may vary depending on the practice type or location, the need for knowledge and comfort when talking with patients to help them make informed decisions is critical. Breast health and screening, including the importance of breast density, happen to be a particular interest of mine. I have participated in educational webinars, invited lectures, and breast cancer awareness media events on this topic in the past.

Continue to: Join forces with imaging centers...

Join forces with imaging centers

2. How can ObGyns and radiologists collaborate most effectively to use screening results to personalize breast care for patients?

Dr. Etkin-Kramer: It is important to have a close relationship with the radiologists that read our patients’ mammograms. We need to be able to easily contact the radiologist and quickly get clarification on a patient’s report or discuss next steps. Imaging centers should consider running outreach programs to educate their referring providers on how to risk assess, with this assessment inclusive of breast density. Dinner lectures or grand round meetings are effective to facilitate communication between the radiology community and the ObGyn community. Finally, as we all know, supplemental screening is often subject to copays and deductibles per insurance coverage. If advocacy groups, who are working to eliminate these types of costs, cannot get insurers to waive these payments, we need a less expensive self-pay option.

Dr. Albright: I definitely have and encourage an open line of communication between my practice and breast radiology, as well as our breast surgeons and cancer center to set up consultations as needed. We also invite our radiologists as guests to monthly practice meetings or grand rounds within our department to further improve access and open communication, as this environment is one in which greater provider education on density and adjunctive screening can be achieved.

Know when to refer a high-risk patient

3. Most ObGyns routinely collect family history and perform formal risk assessment. What do you need to know about referring patients to a high-risk program?

Dr. Etkin-Kramer: It is important as ObGyns to be knowledgeable about breast and ovarian cancer risk assessment and genetic testing for cancer susceptibility genes. Our patients expect that of us. I am comfortable doing risk assessment in my office, but I sometimes refer to other specialists in the community if the patient needs additional counseling. For risk assessment, I look at family and personal history, breast density, and other factors that might lead me to believe the patient might carry a hereditary cancer susceptibility gene, including Ashkenazi Jewish ancestry.¹ When indicated, I check lifetime as well as short-term (5- to 10-year) risk, usually using Breast Cancer Surveillance Consortium (BCSC) or Tyrer-Cuzick/International Breast Cancer Intervention Study (IBIS) models, as these include breast density.

I discuss risk-reducing medications. The US Preventive Services Task Force recommends these agents if my patient’s 5-year risk of breast cancer is 1.67% or greater, and I strongly recommend chemoprevention when the patient’s 5-year BCSC risk exceeds 3%, provided likely benefits exceed risks.^2,3 I discuss adding screening breast MRI if lifetime risk by Tyrer-Cuzick exceeds 20%. (Note that Gail and BCSC models are not recommended to be used to determine risk for purposes of supplemental screening with MRI as they do not consider paternal family history nor age of relatives at diagnosis.)

Dr. Albright: ObGyns should be able to ascertain a pertinent history and identify patients at risk for breast cancer based on their personal history, family history, and breast imaging/biopsy history, if relevant. We also need to improve our discussions of supplemental screening for patients who have heterogeneously dense or extremely dense breast tissue. I sense that some ObGyns may rely heavily on the radiologist to suggest supplemental screening, but patients actually look to Ob­Gyns as their providers to have this knowledge and give them direction.

Since I practice at a large academic medical center, I have the opportunity to refer patients to our Breast Cancer Genetics Program because I may be limited on time for counseling in the office and do not want to miss salient details. With all of the information I have ascertained about the patient, I am able to determine and encourage appropriate screening and assure insurance coverage for adjunctive breast MRI when appropriate.

Continue to: Consider how you order patients’ screening to reduce barriers and cost...

4. How would you suggest reducing barriers when referring patients for supplemental screening, such as MRI for high-risk women or ultrasound for those with dense breasts? Would you prefer it if such screening could be performed without additional script/referral? How does insurance coverage factor in?

Dr. Etkin-Kramer: I would love for a screening mammogram with possible ultrasound, on one script, to be the norm. One of the centers that I work with accepts a script written this way. Further, when a patient receives screening at a freestanding facility as opposed to a hospital, the fee for the supplemental screening may be lower because they do not add on a facility fee.

Dr. Albright: We have an order in our electronic health record that allows for screening mammography but adds on diagnostic mammography/bilateral ultrasonography, if indicated by imaging. I am mostly ordering that option now for all of my screening patients; rarely have I had issues with insurance accepting that script. As for when ordering an MRI, I always try to ensure that I have done the patient’s personal risk assessment and included that lifetime breast cancer risk on the order. If the risk is 20% or higher, I typically do not have any insurance coverage issues. If I am ordering MRI as supplemental screening, I typically order the “Fast MRI” protocol that our center offers. This order incurs a $299 out-of-pocket cost for the patient. Any patient with heterogeneously or extremely dense breasts on mammography should have this option, but it requires patient education, discussion with the provider, and an additional cost. I definitely think that insurers need to consider covering supplemental screening, since breast density is reportable in a majority of the US states and will soon be the national standard.

Pearls for guiding patients

5. How do you discuss breast density and the need for supplemental screening with your patients?

Dr. Etkin-Kramer: I strongly feel that my patients need to know when a screening test has limited ability to do its job. This is the case with dense breasts. Visuals help; when discussing breast density, I like the images supplied by DenseBreast-info.org (FIGURE). I explain the two implications of dense tissue:

• First, dense tissue makes it harder to visualize cancers in the breast—the denser the breasts, the less likely the radiologist can pick up a cancer, so mammographic sensitivity for extremely dense breasts can be as low as 25% to 50%.
• Second, high breast density adds to the risk of developing breast cancer. I explain that supplemental screening will pick up additional cancers in women with dense breasts. For example, breast ultrasound will pick up about 2-3/1000 additional breast cancers per year and MRI or molecular breast imaging (MBI) will pick up much more, perhaps 10/1000.

MRI is more invasive than an ultrasound and uses gadolinium, and MBI has more radiation. Supplemental screening is not endorsed by ACOG’s most recent Committee Opinion from 2017; ⁴ however, patients may choose to have it done. This is where shared-decision making is important.

I strongly recommend that all women’s health care providers complete the CME course on the DenseBreast-info.org website. “ Breast Density: Why It Matters ” is a certified educational program for referring physicians that helps health care professionals learn about breast density, its associated risks, and how best to guide patients regarding breast cancer screening.

Continue to: Dr. Albright...

Dr. Albright: When I discuss breast density, I make sure that patients understand that their mammogram determines the density of their breast tissue. I review that in the higher density categories (heterogeneously dense or extremely dense), there is a higher risk of missing cancer, and that these categories are also associated with a higher risk of breast cancer. I also discuss the potential need for supplemental screening, for which my institution primarily offers Fast MRI. However, we can offer breast ultrasonography instead as an option, especially for those concerned about gadolinium exposure. Our center offers either of these supplemental screenings at a cost of $299. I also review the lack of coverage for supplemental screening by some insurance carriers, as both providers and patients may need to advocate for insurer coverage of adjunct studies.

Educational resources

6. What reference materials, illustrations, or other tools do you use to educate your patients?

Dr. Etkin-Kramer: I frequently use handouts printed from the DenseBreast-info.org website, and there is now a brand new patient fact sheet that I have just started using. I also have an example of breast density categories from fatty replaced to extremely dense on my computer, and I am putting it on a new smart board.

Dr. Albright: The extensive resources available at DenseBreast-info.org can improve both patient and provider knowledge of these important issues, so I suggest patients visit that website, and I use many of the images and visuals to help explain breast density. I even use the materials from the website for educating my resident trainees on breast health and screening. ●

Antibiotics are one of the most frequently prescribed medications in both inpatient and outpatient settings.^1,2 More than 266 million courses of antibiotics are prescribed annually in the outpatient setting; 49.9% of hospitalized patients were prescribed ≥ 1 antibiotic during their hospitalization.^1,2 Among all classes of antibiotics, penicillins are prescribed due to their clinical efficacy, cost-effectiveness, and general safety for all ages. Unfortunately, penicillins also are the most common drug allergy listed in medical records. Patients with this allergy are consistently treated with broad-spectrum antibiotics, have more antibiotic resistant infections, incur higher health care costs, and experience more adverse effects (AEs).^3,4

Drug allergies are distinguished by different immune mechanisms, including IgE-mediated reaction, T-lymphocyte-mediated mild skin reactions, and severe cutaneous adverse reactions (SCAR), or other systemic immune syndromes, such as hemolytic anemia, nephritis, and rash with eosinophilia.³ Although drug allergies should be a concern, compelling evidence shows that > 90% of patients labeled with a penicillin allergy are not allergic to penicillins (and associated β-lactams).^3,4 Although this evidence is growing, clinicians still hesitate to prescribe penicillin, and patients are similarly anxious to take them. This article reviews the health care consequences of penicillin allergy and the application of this information to military medicine and readiness.

Penicillin Allergy Prevalence

Since their approval for public use in 1945, penicillins have been one of the most often prescribed antibiotics due to their clinical efficacy for many types of infections.³ However, 8 to 10% of the US population and up to 15% of hospitalized patients have a documented penicillin allergy, which limits the ability to use these effective antibiotics.^3,4 Once a patient is labeled with a penicillin allergy, many clinicians avoid prescribing all β-lactam antibiotics to patients. Clinicians also avoid prescribing cephalosporins due to the concern for potential cross-reactivity (at a rate of about 2%, which is lower than previously reported).³ These reported allergies are often not clear and range from patients avoiding penicillins because their parents exhibited allergies, they had a symptom that was not likely allergic (ie, nausea, headache, itching with no rash), being told by their parents that they had a rash as a child, or experiencing severe anaphylaxis or other systemic reaction.^3,4 Despite the high rates of documented penicillin allergy, studies now show that most patients do not have a serious allergy; < 1% of the population has a true immune-mediated penicillin allergy.^3,4

Broad-Spectrum Antibiotic Risks

Even though penicillin allergies are often not confirmed, many patients are treated with alternative antibiotics. Unfortunately, most alternative antibiotics are not as effective or as safe as penicillin.^3,4 Twenty percent of hospitalized patients will experience an AE related to their antibiotic; 19.3% of emergency department visits for adverse drug reactions (ADRs) are from antibiotics.^5,6 Sulfonamides, clindamycin, and quinolones were the antibiotics most commonly associated with AEs.⁶

In a large database study over a 3-year period, > 400,000 hospitalizations were analyzed in patients matched for admission type, with and without a penicillin allergy in their medical record.⁷ Those with a documented penicillin allergy had longer hospitalizations; were treated with broad-spectrum antibiotics; and had increased rates of Clostridium difficile (C difficile), methicillin-resistant Staphylococcus aureus (MRSA), and vancomycin-resistant Enterococcus (VRE).^7,8 In addition to being first-line treatment for many common infections, penicillins often are used for dental, perinatal, and perioperative prophylaxis.^1,3 Nearly 25 million antibiotics are prescribed annually by dentists.¹ If a patient has a penicillin allergy listed in their medical record, they will inevitably receive a second- or third-line treatment that is less effective and has higher risks. Common alternative antibiotics include clindamycin, fluoroquinolones, macrolides, and vancomycin.^3,7,8

Clindamycin and fluoroquinolones are associated with C difficile infections.^9,10 Fluoroquinolones come with a boxed warning for known serious ADRs, including tendon rupture, peripheral neuropathy, central nervous system effects, and are known for causing cardiac reactions such as QT prolongation, life-threatening arrhythmias, and cardiovascular death.^11,12 Fluoroquinolones are associated with an increased risk for VRE and MRSA, in more than any other antibiotic classes.^3,7,12,13

Macrolides, such as azithromycin and clarithromycin, are another common class of antibiotics used as an alternative for penicillins. Both are used frequently for upper respiratory infections. Known ADRs to macrolides include gastrointestinal adverse effects (AEs) (ie, nausea, vomiting, diarrhea, and abdominal pain), liver toxicity (ie, abnormal liver function tests, hepatitis, and liver failure), and cardiac risks (ie, QT prolongation and sudden death). When compared with amoxicillin, there was an increased risk for cardiovascular mortality in those patients receiving macrolides.^14,15

Vancomycin is known for its potential to cause “red man syndrome,” an infusion-related reaction causing redness and itching as well as nephrotoxic and hematologic effects requiring close monitoring.³ Vancomycin is less effective than methicillin in clearing MRSA or other sensitive pathogens; however, vancomycin is used in patients with a penicillin allergy label.^16-18 Intrapartum antibiotic use of vancomycin for group B streptococcus infection was associated with clinically significant morbidity and ADRs.^19,20 Perioperatively, patients with penicillin allergies developed more surgical site infections due to the use of second-line antibiotics, such as vancomycin or others.²¹

Cost of Penicillin Allergies

Penicillin allergy plays an important role in rising health care costs. In 2017, health care spending reached 17.9% of the gross domestic product.²² Macy and Contreras demonstrated the significantly higher costs associated with having a reported (and unverified) penicillin allergy in a matched cohort study. Inferred for the extra hospital use, the penicillin allergy group cost the health care system $64,626,630 more than for the group who did not have a penicillin allergy label.⁷ A subsequent study by Macy and Contreras of both inpatient and outpatient settings showed a potential savings of $2,000 per patient per year in health care expenses with the testing and delabeling of penicillin allergies.²³ Use of newer and broad-spectrum antibiotics also are more costly and contribute to higher health care costs.²⁴

When these potential savings are applied to the military insurance population of 9.4 million beneficiaries (TRICARE, including active duty, their dependents, and all retirees participating in the program), the results showed that this could impart a savings of nearly $1.7 billion annually, using the model by Macy and Contreras.^23,25,26

Previously with colleagues, I reviewed penicillin’s role in military history, compiled data from relevant studies from military penicillin allergy rates and delabeling efforts, and calculated the potential economic impact of penicillin allergies along with the benefits of testing.²⁶ Calculations were estimated using the TRICARE beneficiary population (9.4 million) × the estimated prevalence (10%) to get an estimate of 940,000 TRICARE patients with penicillin allergy in their medical record.²⁵ If 90% of those patients were delabeled, this would equal 846,000 TRICARE patients. When multiplied by the potential savings of $2,000 per patient per year, the estimated savings would be $1,692,000,000 annually.^23,26

Current literature provides compelling evidence that all health care plans should use penicillin allergy testing and delabeling programs.^3,23,26 As most patients with a history of penicillin allergy in their medical records do not have a verified allergy, delabeling those who do not have a true allergy will have individual, public health, and cost benefits.^3,7,23,26

Antibiotic Stewardship

Antibiotic stewardship programs are now mandated to combat antibiotic resistance.^3,27 This program is supported by major medical organizations, including the Centers for Disease Control and Prevention, Society for Healthcare Epidemiology of America, Infectious Disease Society of America, and the American Academy of Allergy Asthma and Immunology.³ Given the role of broad-spectrum antibiotics in antibiotic resistance, penicillin allergy testing and delabeling is an important component of these programs.³

In the US, > 2 million people acquire antibiotic resistant infections annually; 23,000 people die of these infections.²⁷ More than 250,000 illnesses and 14,000 deaths annually are due to C difficile.²⁷ There are many factors contributing to the increase in antibiotic resistance; however, one established and consistent factor is the use of broad-spectrum antibiotics. Further, broad-spectrum antibiotics are often used when first-line agents, such as penicillins, cannot be used due to a reported “allergy.” In addition, there are fewer novel antibiotics being developed, and as they are introduced, pathogens develop resistance to these new agents.²⁷

Military Relevance

Infectious diseases have always accompanied military activity.^28-30 Despite preventive programs such as vaccinations, hygiene measures, and prophylactic antibiotics, military personnel are at increased risk for infections due to the military’s mobile nature and crowded living situations.^28-30 This situation has operational relevance from basic training, deployments, and combat operations to peacetime activities.

Military recruits are treated routinely with penicillin G benzathine as standard prophylaxis against streptococcal infections.^26,30 A recent study by the Marine Corps Recruiting Depot in San Diego, California showed that in a cohort of 402 young healthy male recruits, only 5 (1.5%) had a positive reaction to penicillin testing and challenge over a 21-month period.³¹ The delabeled other 397 (98.5%) marine recruits were able to receive benzathine penicillin prophylaxis successfully.³¹ Recruits with a penicillin allergy who had a positive test or were not tested received azithromycin (or erythromycin at some recruit training locations).^26,31 Military members may need to operate in remote or austere locations; the ability to use penicillins is important for readiness.

Evaluation and Management of Reported Penicillin Allergy

Verifying penicillin allergies is an important first step in optimizing medical care and decreasing resistance and ADRs.^3,4,32,33 Although allergists can provide specialized evaluation, due to the high prevalence of penicillin allergy in the US, all health care team members, including clinicians and pharmacists, should be educated about penicillin allergies and be able to implement evaluations in both inpatient and outpatient settings. Reactions to any of the penicillins should be considered, including the natural penicillins (penicillin V, etc), antistaphylococcal penicillins (dicloxacillin), aminopenicillins (amoxicillin and ampicillin), and extended-spectrum penicillins (piperacillin).³ A thorough history, including the prior reaction (age, type of reaction) and subsequent tolerance are helpful in stratifying patients.^3,26

Patient Risk Levels

Based on the clinical history, patients would fall into 4 categories from low risk, medium risk, high risk, to do not test/use.^3,32,33 Low-risk patients are those who report mild or nonallergic symptoms (ie, gastrointestinal symptoms, headache, yeast infection, etc), remote cutaneous reactions (> 10 years), or in those with a family history of penicillin allergy.^3,32,33 Low-risk patients often can be safely tested with an oral challenge. Although there are different approaches to the oral challenge, a single amoxicillin dose of 250 mg followed by 1 hour of direct monitoring is usually sufficient.^3,32,33

Medium-risk patients have a more recent (< 1 year) history of pruritic rashes, urticaria, and/or angioedema without a history of severe or systemic reactions. These patients benefit from negative skin testing prior to an oral challenge, which can be performed by trained clinicians or pharmacists or an allergist. However, due to limited availability of skin testing and the potential for false positive testing with skin tests, a single dose or graded challenge would be a reasonable approach as well.^3,32,33

High-risk patients are those with severe symptoms (anaphylaxis), a history of reactions to other β-lactam antibiotics, and/or recurrent reactions to antibiotics. These patients benefit from a formal evaluation by an allergist and skin testing prior to challenge.^3,32,33 Testing and/or challenge should not be performed in patients who report a history of severe cutaneous reactions (blistering rash, such as Stevens Johnson syndrome), hemolytic anemia, serum sickness, drug fever, and other organ dysfunction.^3,4,31,32

Conclusions

Penicillin allergies are an important barrier to effective antibiotic treatments and are associated with worse outcomes and higher economic costs.^3,7,23,26,34 Therefore, in addition to vaccinations, infection control measures, and public health education, penicillin allergy verification and delabeling programs should be a proactive component of military medical readiness and all antibiotic stewardship initiatives in all health care settings.²⁹ Given the many issues and negative impact of having a penicillin allergy label, penicillin delabeling will allow service members to be treated with the necessary antibiotics with fewer adverse complications, and return them to health and readiness for operational duties. In the current standardization of the Defense Health Agency, implementing this program across all services would have significant clinical, public health, and cost benefits for patients, the health care team, taxpayers, and the community at large.

Many patients report an allergy to penicillin, but only a small portion have a current true immune-mediated allergy. Given the clinical, public health, and economic costs associated with a penicillin allergy label, evaluation and clearance of penicillin allergies is a simple method that would improve clinical outcomes, decrease AEs to high-risk alternative broad-spectrum antibiotics, and prevent the spread of antibiotic resistance. In the military, penicillin delabeling improves readiness with optimal antibiotic options and avoidance of unnecessary risks of using alternative antibiotics, expediting return to full duty for military personnel.

Antibiotics are one of the most frequently prescribed medications in both inpatient and outpatient settings.^1,2 More than 266 million courses of antibiotics are prescribed annually in the outpatient setting; 49.9% of hospitalized patients were prescribed ≥ 1 antibiotic during their hospitalization.^1,2 Among all classes of antibiotics, penicillins are prescribed due to their clinical efficacy, cost-effectiveness, and general safety for all ages. Unfortunately, penicillins also are the most common drug allergy listed in medical records. Patients with this allergy are consistently treated with broad-spectrum antibiotics, have more antibiotic resistant infections, incur higher health care costs, and experience more adverse effects (AEs).^3,4

Drug allergies are distinguished by different immune mechanisms, including IgE-mediated reaction, T-lymphocyte-mediated mild skin reactions, and severe cutaneous adverse reactions (SCAR), or other systemic immune syndromes, such as hemolytic anemia, nephritis, and rash with eosinophilia.³ Although drug allergies should be a concern, compelling evidence shows that > 90% of patients labeled with a penicillin allergy are not allergic to penicillins (and associated β-lactams).^3,4 Although this evidence is growing, clinicians still hesitate to prescribe penicillin, and patients are similarly anxious to take them. This article reviews the health care consequences of penicillin allergy and the application of this information to military medicine and readiness.

Penicillin Allergy Prevalence

Since their approval for public use in 1945, penicillins have been one of the most often prescribed antibiotics due to their clinical efficacy for many types of infections.³ However, 8 to 10% of the US population and up to 15% of hospitalized patients have a documented penicillin allergy, which limits the ability to use these effective antibiotics.^3,4 Once a patient is labeled with a penicillin allergy, many clinicians avoid prescribing all β-lactam antibiotics to patients. Clinicians also avoid prescribing cephalosporins due to the concern for potential cross-reactivity (at a rate of about 2%, which is lower than previously reported).³ These reported allergies are often not clear and range from patients avoiding penicillins because their parents exhibited allergies, they had a symptom that was not likely allergic (ie, nausea, headache, itching with no rash), being told by their parents that they had a rash as a child, or experiencing severe anaphylaxis or other systemic reaction.^3,4 Despite the high rates of documented penicillin allergy, studies now show that most patients do not have a serious allergy; < 1% of the population has a true immune-mediated penicillin allergy.^3,4

Broad-Spectrum Antibiotic Risks

Even though penicillin allergies are often not confirmed, many patients are treated with alternative antibiotics. Unfortunately, most alternative antibiotics are not as effective or as safe as penicillin.^3,4 Twenty percent of hospitalized patients will experience an AE related to their antibiotic; 19.3% of emergency department visits for adverse drug reactions (ADRs) are from antibiotics.^5,6 Sulfonamides, clindamycin, and quinolones were the antibiotics most commonly associated with AEs.⁶

In a large database study over a 3-year period, > 400,000 hospitalizations were analyzed in patients matched for admission type, with and without a penicillin allergy in their medical record.⁷ Those with a documented penicillin allergy had longer hospitalizations; were treated with broad-spectrum antibiotics; and had increased rates of Clostridium difficile (C difficile), methicillin-resistant Staphylococcus aureus (MRSA), and vancomycin-resistant Enterococcus (VRE).^7,8 In addition to being first-line treatment for many common infections, penicillins often are used for dental, perinatal, and perioperative prophylaxis.^1,3 Nearly 25 million antibiotics are prescribed annually by dentists.¹ If a patient has a penicillin allergy listed in their medical record, they will inevitably receive a second- or third-line treatment that is less effective and has higher risks. Common alternative antibiotics include clindamycin, fluoroquinolones, macrolides, and vancomycin.^3,7,8

Clindamycin and fluoroquinolones are associated with C difficile infections.^9,10 Fluoroquinolones come with a boxed warning for known serious ADRs, including tendon rupture, peripheral neuropathy, central nervous system effects, and are known for causing cardiac reactions such as QT prolongation, life-threatening arrhythmias, and cardiovascular death.^11,12 Fluoroquinolones are associated with an increased risk for VRE and MRSA, in more than any other antibiotic classes.^3,7,12,13

Macrolides, such as azithromycin and clarithromycin, are another common class of antibiotics used as an alternative for penicillins. Both are used frequently for upper respiratory infections. Known ADRs to macrolides include gastrointestinal adverse effects (AEs) (ie, nausea, vomiting, diarrhea, and abdominal pain), liver toxicity (ie, abnormal liver function tests, hepatitis, and liver failure), and cardiac risks (ie, QT prolongation and sudden death). When compared with amoxicillin, there was an increased risk for cardiovascular mortality in those patients receiving macrolides.^14,15

Vancomycin is known for its potential to cause “red man syndrome,” an infusion-related reaction causing redness and itching as well as nephrotoxic and hematologic effects requiring close monitoring.³ Vancomycin is less effective than methicillin in clearing MRSA or other sensitive pathogens; however, vancomycin is used in patients with a penicillin allergy label.^16-18 Intrapartum antibiotic use of vancomycin for group B streptococcus infection was associated with clinically significant morbidity and ADRs.^19,20 Perioperatively, patients with penicillin allergies developed more surgical site infections due to the use of second-line antibiotics, such as vancomycin or others.²¹

Cost of Penicillin Allergies

Penicillin allergy plays an important role in rising health care costs. In 2017, health care spending reached 17.9% of the gross domestic product.²² Macy and Contreras demonstrated the significantly higher costs associated with having a reported (and unverified) penicillin allergy in a matched cohort study. Inferred for the extra hospital use, the penicillin allergy group cost the health care system $64,626,630 more than for the group who did not have a penicillin allergy label.⁷ A subsequent study by Macy and Contreras of both inpatient and outpatient settings showed a potential savings of $2,000 per patient per year in health care expenses with the testing and delabeling of penicillin allergies.²³ Use of newer and broad-spectrum antibiotics also are more costly and contribute to higher health care costs.²⁴

When these potential savings are applied to the military insurance population of 9.4 million beneficiaries (TRICARE, including active duty, their dependents, and all retirees participating in the program), the results showed that this could impart a savings of nearly $1.7 billion annually, using the model by Macy and Contreras.^23,25,26

Previously with colleagues, I reviewed penicillin’s role in military history, compiled data from relevant studies from military penicillin allergy rates and delabeling efforts, and calculated the potential economic impact of penicillin allergies along with the benefits of testing.²⁶ Calculations were estimated using the TRICARE beneficiary population (9.4 million) × the estimated prevalence (10%) to get an estimate of 940,000 TRICARE patients with penicillin allergy in their medical record.²⁵ If 90% of those patients were delabeled, this would equal 846,000 TRICARE patients. When multiplied by the potential savings of $2,000 per patient per year, the estimated savings would be $1,692,000,000 annually.^23,26

Current literature provides compelling evidence that all health care plans should use penicillin allergy testing and delabeling programs.^3,23,26 As most patients with a history of penicillin allergy in their medical records do not have a verified allergy, delabeling those who do not have a true allergy will have individual, public health, and cost benefits.^3,7,23,26

Antibiotic Stewardship

Antibiotic stewardship programs are now mandated to combat antibiotic resistance.^3,27 This program is supported by major medical organizations, including the Centers for Disease Control and Prevention, Society for Healthcare Epidemiology of America, Infectious Disease Society of America, and the American Academy of Allergy Asthma and Immunology.³ Given the role of broad-spectrum antibiotics in antibiotic resistance, penicillin allergy testing and delabeling is an important component of these programs.³

In the US, > 2 million people acquire antibiotic resistant infections annually; 23,000 people die of these infections.²⁷ More than 250,000 illnesses and 14,000 deaths annually are due to C difficile.²⁷ There are many factors contributing to the increase in antibiotic resistance; however, one established and consistent factor is the use of broad-spectrum antibiotics. Further, broad-spectrum antibiotics are often used when first-line agents, such as penicillins, cannot be used due to a reported “allergy.” In addition, there are fewer novel antibiotics being developed, and as they are introduced, pathogens develop resistance to these new agents.²⁷

Military Relevance

Infectious diseases have always accompanied military activity.^28-30 Despite preventive programs such as vaccinations, hygiene measures, and prophylactic antibiotics, military personnel are at increased risk for infections due to the military’s mobile nature and crowded living situations.^28-30 This situation has operational relevance from basic training, deployments, and combat operations to peacetime activities.

Military recruits are treated routinely with penicillin G benzathine as standard prophylaxis against streptococcal infections.^26,30 A recent study by the Marine Corps Recruiting Depot in San Diego, California showed that in a cohort of 402 young healthy male recruits, only 5 (1.5%) had a positive reaction to penicillin testing and challenge over a 21-month period.³¹ The delabeled other 397 (98.5%) marine recruits were able to receive benzathine penicillin prophylaxis successfully.³¹ Recruits with a penicillin allergy who had a positive test or were not tested received azithromycin (or erythromycin at some recruit training locations).^26,31 Military members may need to operate in remote or austere locations; the ability to use penicillins is important for readiness.

Evaluation and Management of Reported Penicillin Allergy

Verifying penicillin allergies is an important first step in optimizing medical care and decreasing resistance and ADRs.^3,4,32,33 Although allergists can provide specialized evaluation, due to the high prevalence of penicillin allergy in the US, all health care team members, including clinicians and pharmacists, should be educated about penicillin allergies and be able to implement evaluations in both inpatient and outpatient settings. Reactions to any of the penicillins should be considered, including the natural penicillins (penicillin V, etc), antistaphylococcal penicillins (dicloxacillin), aminopenicillins (amoxicillin and ampicillin), and extended-spectrum penicillins (piperacillin).³ A thorough history, including the prior reaction (age, type of reaction) and subsequent tolerance are helpful in stratifying patients.^3,26

Patient Risk Levels

Based on the clinical history, patients would fall into 4 categories from low risk, medium risk, high risk, to do not test/use.^3,32,33 Low-risk patients are those who report mild or nonallergic symptoms (ie, gastrointestinal symptoms, headache, yeast infection, etc), remote cutaneous reactions (> 10 years), or in those with a family history of penicillin allergy.^3,32,33 Low-risk patients often can be safely tested with an oral challenge. Although there are different approaches to the oral challenge, a single amoxicillin dose of 250 mg followed by 1 hour of direct monitoring is usually sufficient.^3,32,33

Medium-risk patients have a more recent (< 1 year) history of pruritic rashes, urticaria, and/or angioedema without a history of severe or systemic reactions. These patients benefit from negative skin testing prior to an oral challenge, which can be performed by trained clinicians or pharmacists or an allergist. However, due to limited availability of skin testing and the potential for false positive testing with skin tests, a single dose or graded challenge would be a reasonable approach as well.^3,32,33

High-risk patients are those with severe symptoms (anaphylaxis), a history of reactions to other β-lactam antibiotics, and/or recurrent reactions to antibiotics. These patients benefit from a formal evaluation by an allergist and skin testing prior to challenge.^3,32,33 Testing and/or challenge should not be performed in patients who report a history of severe cutaneous reactions (blistering rash, such as Stevens Johnson syndrome), hemolytic anemia, serum sickness, drug fever, and other organ dysfunction.^3,4,31,32

Conclusions

Penicillin allergies are an important barrier to effective antibiotic treatments and are associated with worse outcomes and higher economic costs.^3,7,23,26,34 Therefore, in addition to vaccinations, infection control measures, and public health education, penicillin allergy verification and delabeling programs should be a proactive component of military medical readiness and all antibiotic stewardship initiatives in all health care settings.²⁹ Given the many issues and negative impact of having a penicillin allergy label, penicillin delabeling will allow service members to be treated with the necessary antibiotics with fewer adverse complications, and return them to health and readiness for operational duties. In the current standardization of the Defense Health Agency, implementing this program across all services would have significant clinical, public health, and cost benefits for patients, the health care team, taxpayers, and the community at large.

Many patients report an allergy to penicillin, but only a small portion have a current true immune-mediated allergy. Given the clinical, public health, and economic costs associated with a penicillin allergy label, evaluation and clearance of penicillin allergies is a simple method that would improve clinical outcomes, decrease AEs to high-risk alternative broad-spectrum antibiotics, and prevent the spread of antibiotic resistance. In the military, penicillin delabeling improves readiness with optimal antibiotic options and avoidance of unnecessary risks of using alternative antibiotics, expediting return to full duty for military personnel.

Antibiotics are one of the most frequently prescribed medications in both inpatient and outpatient settings.^1,2 More than 266 million courses of antibiotics are prescribed annually in the outpatient setting; 49.9% of hospitalized patients were prescribed ≥ 1 antibiotic during their hospitalization.^1,2 Among all classes of antibiotics, penicillins are prescribed due to their clinical efficacy, cost-effectiveness, and general safety for all ages. Unfortunately, penicillins also are the most common drug allergy listed in medical records. Patients with this allergy are consistently treated with broad-spectrum antibiotics, have more antibiotic resistant infections, incur higher health care costs, and experience more adverse effects (AEs).^3,4

Drug allergies are distinguished by different immune mechanisms, including IgE-mediated reaction, T-lymphocyte-mediated mild skin reactions, and severe cutaneous adverse reactions (SCAR), or other systemic immune syndromes, such as hemolytic anemia, nephritis, and rash with eosinophilia.³ Although drug allergies should be a concern, compelling evidence shows that > 90% of patients labeled with a penicillin allergy are not allergic to penicillins (and associated β-lactams).^3,4 Although this evidence is growing, clinicians still hesitate to prescribe penicillin, and patients are similarly anxious to take them. This article reviews the health care consequences of penicillin allergy and the application of this information to military medicine and readiness.

Penicillin Allergy Prevalence

Since their approval for public use in 1945, penicillins have been one of the most often prescribed antibiotics due to their clinical efficacy for many types of infections.³ However, 8 to 10% of the US population and up to 15% of hospitalized patients have a documented penicillin allergy, which limits the ability to use these effective antibiotics.^3,4 Once a patient is labeled with a penicillin allergy, many clinicians avoid prescribing all β-lactam antibiotics to patients. Clinicians also avoid prescribing cephalosporins due to the concern for potential cross-reactivity (at a rate of about 2%, which is lower than previously reported).³ These reported allergies are often not clear and range from patients avoiding penicillins because their parents exhibited allergies, they had a symptom that was not likely allergic (ie, nausea, headache, itching with no rash), being told by their parents that they had a rash as a child, or experiencing severe anaphylaxis or other systemic reaction.^3,4 Despite the high rates of documented penicillin allergy, studies now show that most patients do not have a serious allergy; < 1% of the population has a true immune-mediated penicillin allergy.^3,4

Broad-Spectrum Antibiotic Risks

Even though penicillin allergies are often not confirmed, many patients are treated with alternative antibiotics. Unfortunately, most alternative antibiotics are not as effective or as safe as penicillin.^3,4 Twenty percent of hospitalized patients will experience an AE related to their antibiotic; 19.3% of emergency department visits for adverse drug reactions (ADRs) are from antibiotics.^5,6 Sulfonamides, clindamycin, and quinolones were the antibiotics most commonly associated with AEs.⁶

In a large database study over a 3-year period, > 400,000 hospitalizations were analyzed in patients matched for admission type, with and without a penicillin allergy in their medical record.⁷ Those with a documented penicillin allergy had longer hospitalizations; were treated with broad-spectrum antibiotics; and had increased rates of Clostridium difficile (C difficile), methicillin-resistant Staphylococcus aureus (MRSA), and vancomycin-resistant Enterococcus (VRE).^7,8 In addition to being first-line treatment for many common infections, penicillins often are used for dental, perinatal, and perioperative prophylaxis.^1,3 Nearly 25 million antibiotics are prescribed annually by dentists.¹ If a patient has a penicillin allergy listed in their medical record, they will inevitably receive a second- or third-line treatment that is less effective and has higher risks. Common alternative antibiotics include clindamycin, fluoroquinolones, macrolides, and vancomycin.^3,7,8

Clindamycin and fluoroquinolones are associated with C difficile infections.^9,10 Fluoroquinolones come with a boxed warning for known serious ADRs, including tendon rupture, peripheral neuropathy, central nervous system effects, and are known for causing cardiac reactions such as QT prolongation, life-threatening arrhythmias, and cardiovascular death.^11,12 Fluoroquinolones are associated with an increased risk for VRE and MRSA, in more than any other antibiotic classes.^3,7,12,13

Macrolides, such as azithromycin and clarithromycin, are another common class of antibiotics used as an alternative for penicillins. Both are used frequently for upper respiratory infections. Known ADRs to macrolides include gastrointestinal adverse effects (AEs) (ie, nausea, vomiting, diarrhea, and abdominal pain), liver toxicity (ie, abnormal liver function tests, hepatitis, and liver failure), and cardiac risks (ie, QT prolongation and sudden death). When compared with amoxicillin, there was an increased risk for cardiovascular mortality in those patients receiving macrolides.^14,15

Vancomycin is known for its potential to cause “red man syndrome,” an infusion-related reaction causing redness and itching as well as nephrotoxic and hematologic effects requiring close monitoring.³ Vancomycin is less effective than methicillin in clearing MRSA or other sensitive pathogens; however, vancomycin is used in patients with a penicillin allergy label.^16-18 Intrapartum antibiotic use of vancomycin for group B streptococcus infection was associated with clinically significant morbidity and ADRs.^19,20 Perioperatively, patients with penicillin allergies developed more surgical site infections due to the use of second-line antibiotics, such as vancomycin or others.²¹

Cost of Penicillin Allergies

Penicillin allergy plays an important role in rising health care costs. In 2017, health care spending reached 17.9% of the gross domestic product.²² Macy and Contreras demonstrated the significantly higher costs associated with having a reported (and unverified) penicillin allergy in a matched cohort study. Inferred for the extra hospital use, the penicillin allergy group cost the health care system $64,626,630 more than for the group who did not have a penicillin allergy label.⁷ A subsequent study by Macy and Contreras of both inpatient and outpatient settings showed a potential savings of $2,000 per patient per year in health care expenses with the testing and delabeling of penicillin allergies.²³ Use of newer and broad-spectrum antibiotics also are more costly and contribute to higher health care costs.²⁴

When these potential savings are applied to the military insurance population of 9.4 million beneficiaries (TRICARE, including active duty, their dependents, and all retirees participating in the program), the results showed that this could impart a savings of nearly $1.7 billion annually, using the model by Macy and Contreras.^23,25,26

Previously with colleagues, I reviewed penicillin’s role in military history, compiled data from relevant studies from military penicillin allergy rates and delabeling efforts, and calculated the potential economic impact of penicillin allergies along with the benefits of testing.²⁶ Calculations were estimated using the TRICARE beneficiary population (9.4 million) × the estimated prevalence (10%) to get an estimate of 940,000 TRICARE patients with penicillin allergy in their medical record.²⁵ If 90% of those patients were delabeled, this would equal 846,000 TRICARE patients. When multiplied by the potential savings of $2,000 per patient per year, the estimated savings would be $1,692,000,000 annually.^23,26

Current literature provides compelling evidence that all health care plans should use penicillin allergy testing and delabeling programs.^3,23,26 As most patients with a history of penicillin allergy in their medical records do not have a verified allergy, delabeling those who do not have a true allergy will have individual, public health, and cost benefits.^3,7,23,26

Antibiotic Stewardship

Antibiotic stewardship programs are now mandated to combat antibiotic resistance.^3,27 This program is supported by major medical organizations, including the Centers for Disease Control and Prevention, Society for Healthcare Epidemiology of America, Infectious Disease Society of America, and the American Academy of Allergy Asthma and Immunology.³ Given the role of broad-spectrum antibiotics in antibiotic resistance, penicillin allergy testing and delabeling is an important component of these programs.³

In the US, > 2 million people acquire antibiotic resistant infections annually; 23,000 people die of these infections.²⁷ More than 250,000 illnesses and 14,000 deaths annually are due to C difficile.²⁷ There are many factors contributing to the increase in antibiotic resistance; however, one established and consistent factor is the use of broad-spectrum antibiotics. Further, broad-spectrum antibiotics are often used when first-line agents, such as penicillins, cannot be used due to a reported “allergy.” In addition, there are fewer novel antibiotics being developed, and as they are introduced, pathogens develop resistance to these new agents.²⁷

Military Relevance

Infectious diseases have always accompanied military activity.^28-30 Despite preventive programs such as vaccinations, hygiene measures, and prophylactic antibiotics, military personnel are at increased risk for infections due to the military’s mobile nature and crowded living situations.^28-30 This situation has operational relevance from basic training, deployments, and combat operations to peacetime activities.

Military recruits are treated routinely with penicillin G benzathine as standard prophylaxis against streptococcal infections.^26,30 A recent study by the Marine Corps Recruiting Depot in San Diego, California showed that in a cohort of 402 young healthy male recruits, only 5 (1.5%) had a positive reaction to penicillin testing and challenge over a 21-month period.³¹ The delabeled other 397 (98.5%) marine recruits were able to receive benzathine penicillin prophylaxis successfully.³¹ Recruits with a penicillin allergy who had a positive test or were not tested received azithromycin (or erythromycin at some recruit training locations).^26,31 Military members may need to operate in remote or austere locations; the ability to use penicillins is important for readiness.

Evaluation and Management of Reported Penicillin Allergy

Verifying penicillin allergies is an important first step in optimizing medical care and decreasing resistance and ADRs.^3,4,32,33 Although allergists can provide specialized evaluation, due to the high prevalence of penicillin allergy in the US, all health care team members, including clinicians and pharmacists, should be educated about penicillin allergies and be able to implement evaluations in both inpatient and outpatient settings. Reactions to any of the penicillins should be considered, including the natural penicillins (penicillin V, etc), antistaphylococcal penicillins (dicloxacillin), aminopenicillins (amoxicillin and ampicillin), and extended-spectrum penicillins (piperacillin).³ A thorough history, including the prior reaction (age, type of reaction) and subsequent tolerance are helpful in stratifying patients.^3,26

Patient Risk Levels

Based on the clinical history, patients would fall into 4 categories from low risk, medium risk, high risk, to do not test/use.^3,32,33 Low-risk patients are those who report mild or nonallergic symptoms (ie, gastrointestinal symptoms, headache, yeast infection, etc), remote cutaneous reactions (> 10 years), or in those with a family history of penicillin allergy.^3,32,33 Low-risk patients often can be safely tested with an oral challenge. Although there are different approaches to the oral challenge, a single amoxicillin dose of 250 mg followed by 1 hour of direct monitoring is usually sufficient.^3,32,33

Medium-risk patients have a more recent (< 1 year) history of pruritic rashes, urticaria, and/or angioedema without a history of severe or systemic reactions. These patients benefit from negative skin testing prior to an oral challenge, which can be performed by trained clinicians or pharmacists or an allergist. However, due to limited availability of skin testing and the potential for false positive testing with skin tests, a single dose or graded challenge would be a reasonable approach as well.^3,32,33

High-risk patients are those with severe symptoms (anaphylaxis), a history of reactions to other β-lactam antibiotics, and/or recurrent reactions to antibiotics. These patients benefit from a formal evaluation by an allergist and skin testing prior to challenge.^3,32,33 Testing and/or challenge should not be performed in patients who report a history of severe cutaneous reactions (blistering rash, such as Stevens Johnson syndrome), hemolytic anemia, serum sickness, drug fever, and other organ dysfunction.^3,4,31,32

Conclusions

Penicillin allergies are an important barrier to effective antibiotic treatments and are associated with worse outcomes and higher economic costs.^3,7,23,26,34 Therefore, in addition to vaccinations, infection control measures, and public health education, penicillin allergy verification and delabeling programs should be a proactive component of military medical readiness and all antibiotic stewardship initiatives in all health care settings.²⁹ Given the many issues and negative impact of having a penicillin allergy label, penicillin delabeling will allow service members to be treated with the necessary antibiotics with fewer adverse complications, and return them to health and readiness for operational duties. In the current standardization of the Defense Health Agency, implementing this program across all services would have significant clinical, public health, and cost benefits for patients, the health care team, taxpayers, and the community at large.

Many patients report an allergy to penicillin, but only a small portion have a current true immune-mediated allergy. Given the clinical, public health, and economic costs associated with a penicillin allergy label, evaluation and clearance of penicillin allergies is a simple method that would improve clinical outcomes, decrease AEs to high-risk alternative broad-spectrum antibiotics, and prevent the spread of antibiotic resistance. In the military, penicillin delabeling improves readiness with optimal antibiotic options and avoidance of unnecessary risks of using alternative antibiotics, expediting return to full duty for military personnel.

Serotonin, or 5-hydroxytryptamine (5-HT), is a chemical neurotransmitter in the central and peripheral nervous systems that was discovered in 1940s. ¹ O ne of the most widely studied chemical messengers , serotonin influences many physiologic functions in humans, including regulation of mood, sleep-wake cycle, appetite suppression, memory, emesis, breathing, cognition, blood coagulation, libido, and many other functions. ² In 1992, Insel and colleagues first document ed the toxic symptoms produced from too much serotonin in the central and peripheral nervous systems , naming it serotonin syndrome. ^3,4

Serotonin Syndrome

Experts in the fields of psychiatry, pharmacy, and toxicology refer to these symptoms as serotonin toxicity, because the symptoms result from the toxic effects of too much serotonin.^5-9 The term toxicity instead of syndrome “clarifies that it is a form of poisoning, just as lithium toxicity is a form of poisoning.”⁶ Therefore, serotonin toxicity (ST) can develop with administration of any serotonin-enhancing medication, including therapeutic use, polypharmacy, or accidental/intentional drug overdose.

The incidence of ST has increased over the past decade.^5,6,10,11 Several reasons explain this increase: (1) ST mirrors the increase in depression in the US populations^10,12,13; (2) There has been an increase in off-label antidepressant prescribing by both primary care and mental health providers^14-16; (3) the increased use of illicit drugs¹³; (4) an increase in suicide attempts with antidepressants¹⁷; and (5) increased use of opioids for pain management, including both prescription and illicit use.^11,14 This paper reviews the potential lethal combinations of commonly prescribed medications used to treat both veteran and nonveteran patients and includes the latest information on offending medications; a presentation of symptoms from in utero to adult; diagnostic criteria; and recommended treatments.

The Veterans Health Administration (VHA) and non-VHA health care providers can play a key role in identifying and preventing serotonin syndrome/ST by keeping abreast of the latest updates of potentially lethal drug combinations. Commonly prescribed medications with the potential for a reaction include antidepressants, anxiolytics, pain medications, antinausea medications, herbal medications, and over-the-counter (OTC) medications, such as cough suppressants. Patients may be at increased risk for ST due to the growth of polypharmacy management of comorbidities.

Antidepressants

Over the past decade, antidepressant use has increased substantially in the US,United Kingdom, and Canada.¹⁴ Also the types of antidepressants prescribed has changed and been replaced with the newer agents. The selective serotonin reuptake inhibitors (SSRIs) and selective norepinephrine reuptake inhibitors (SNRIs) have replaced the older tricyclics (TCAs) and monoamine oxidase inhibitors (MAOIs) as first-line treatments for depression due to their improved comparative efficacy, reduced mortality following overdose, adverse effects (AEs) that are more tolerable for most patients, and the SSRIs have no anticholinergic properties (except paroxetine) (Table 1).¹⁸

In 2017 the National Institute of Mental Health reported that about 17 million adults and 3 million adolescents (aged 11-18 years) experienced at least 1 episode of major depression.¹⁹ About 40% of US veterans will experience depression, which is 3 times higher than the rate of the general US population.¹² A random sampling survey conducted of about 17,000 active-duty service members by the US Department of Defense (DoD) from November 2015 to April 2016 revealed 9.4% reported depression.²⁰ Antidepressant usage in the US and among veterans continues to increase.^12,16 In 2018, the list of top US prescribed drugs, included sertraline (14th), citalopram (21st), trazodone (24th), and escitalopram (26th).²¹ Antidepressant prescribing in the US increased 18% from 2012 to 2017.²² This trend also continues within the military with a 40% increase of antidepressant use in the past decade.¹⁶

One reason for the increase in antidepressant use is off-label prescribing.^14,23 A sampling of about 2 billion psychiatric outpatient visits in a western portion of the US found 12.9% of the prescriptions filled were off-label.¹⁵ In Minnesota, off-label prescribing of antidepressants was found to contribute to an increase in drug interactions in elderly nursing home residents.²⁴ An investigation by the Military Times of the military community revealed off-label prescribing occurs not only with antidepressant medications, but also with anticonvulsants, antipsychotics, anti-anxiety drugs, and antiepileptic medications.¹⁴

A case report that brought ST to the forefront occurred in the 1980s and involved a college student.²⁵ She was initially diagnosed with the flu. Her symptoms progressed over a 24-hour period despite treatment, leading to seizures, hyperthermia, generalized clonus, muscle rigidity, respiratory failure, and death because of unrecognized ST. Her combination of serotonin-elevating drugs included meperidine, phenelzine, chlorpheniramine, and haldol. On autopsy, there were traces of cocaine found in some of her tissue samples.

Pathophysiology

Tryptophan is a precursor of serotonin and must be ingested from foods, including meats, dairy, fruits, and seeds. About 90% of all serotonin is made in the gastrointestinal epithelium and is the major component of the brain-gut axis.²⁶ Serotonin cannot cross the blood-brain barrier; therefore, it is synthesized and stored in presynaptic terminals around the midline of the brainstem.^1,26 Transport of serotonin is provided by serotonin transporter (SERT).^1,26,27 Once released, serotonin can either stimulate postsynaptic neuron receptors or is taken up into the presynaptic terminals for reuse. SSRI antidepressants, such as citalopram and paroxetine inhibit the reuptake of serotonin by binding to 2 different sites on the SERT thus allowing more available serotonin to be accessible to other neurons.²⁷ There are 7 families of serotonin receptors, 5-HT1 to 5-HT7 and at least 15 mammalian subtypes.^28,29 The majority of these receptors have been implicated in depression or depressive-like behavior as evidenced by the efficacy of increasing extracellular serotonin for the treatment of depression with SSRIs, SNRIs, TCAs, and MAOIs.²⁹ Three of the most studied receptors include 5-HT_IA,5-HT_1B,and 5-HT_2A.

Etiology

Most serotonin-induced drug fatalities occur when combining serotonergic drugs that work through different pathways (Table 2).³⁰ The most toxic combination of serotonin-enhancing drugs includes MAOIs taken with SSRIs or SNRIs, or a combination of 2 MAOIs.^5-9

Other potentially lethal combinations may includepolypharmacy with antidepressants, pain medications, OTC medications, and illicit drugs. Linezolid, a new synthetic antimicrobial, is considered to be a weak MAOI. Therefore, prescribing it with other serotonin-elevating agents has been reported to precipitate ST.¹⁸

Most cases of ST do not require hospitalization and can be managed by stopping the medication or decreasing the dose. Therapeutic doses of a single drug are highly unlikely to cause toxicity, although there have been reported cases of patients who are sensitive or more susceptible and develop symptoms after administration of a single agent and/or a dosage increase.

Delayed ST reactions have occurred because of a prolonged half-life of a drug, iron deficiency anemia, and coingestion of shorter acting serotonin antagonists.³¹ Most antidepressants have a short half-life (< 24 hours)except for fluoxetine. A decrease in iron may contribute to ST because iron is needed to process serotonin from tryptophan. An example of 2 shorter-acting serotonin antagonists include cyproheptadine and olanzapine. Cyproheptadine is used in the treatment of ST, and olanzapine is an antipsychotic.

Symptoms

Symptoms of ST range from mild to severe and include a combination of neuromuscular, autonomic, and mental status changes (Table 3).^5,10 Mild symptoms of ST can start within 1 to 2 hours after ingesting a medication that increases serotonin to a toxic state unless the drug has a long half-life (eg, fluoxetine). Sometimes mild symptoms of ST can be difficult to distinguish from common drug AEs, flu symptoms, or viruses. Patients taking therapeutic doses of SSRIs can experience serotonin symptoms, such as lower limb hyperreflexia or a few beats of ankle clonus without being toxic. One thing to remember is that not all patients will start with mild symptoms and may present in moderate or severe distress.

Moderate-to-severe ST symptoms require hospitalization, usually in the intensive care unit (ICU). At this stage, clonus progresses from the lower extremities to the upper body and becomes more generalized. Ocular clonus can be continuous, intermittent, or have a ping pong effect (short cycle, periodic, alternating lateral gaze).

Severe ST is life threatening and leads to multiorgan failure within hours if not treated. The patient is intubated to assist with breathing and sedated because excess agitation and muscular tremors can increase temperature, which is already elevated by the time the symptoms reach the severe state. Of note, hyperthermia is due to a noninfectious elevation of body temperature from hypertonicity, agitation, and muscle rigidity.A true core temperature > 105.8°F causes irreversible cell damage, cerebral injury, and death.^32,33 The patient can develop seizures and a coma. Multiorgan failure occurs, including rhabdomyolysis, myoglobinuria, renal failure, metabolic acidosis, acute respiratory distress, and disseminated intravascular coagulation.

Diagnosis

The diagnosis of ST is clinical and based on a history of ingesting serotonin-elevating medications and physical findings as per Hunter Serotonin Toxicity Criteria³⁴ (Table 4). An in-depth history needs to include previous and current prescriptions, indications of the prescriptions (eg, therapeutic, increase in dosage, suicide intent), OTC medications, and illicit drug use. Early recognition of symptoms, identification of serotonergic medications, and appropriate resuscitative measures lead to more successful outcomes. A serotonin drug level is ineffective and does not correlate with the dosage since serotonin does not cross the blood-brain barrier.

The type of drug determines the length and response of the episode. The drug(s) elimination half-lives need to be calculated along with the pharmacokinetic or pharmacodynamics; agonist, antagonist, reuptake inhibitor, etc. Many drugs have half-lives of < 24 hours; therefore, reducing or eliminating the offending drug(s) will result in a steady reduction of symptoms.Exceptions include medications with a longer activity, such as the irreversible MAOIs (eg, phenelzine, isocarboxazid) and drugs with a longer half-life, such as fluoxetine. These types of medications may have been stopped weeks earlier and may prolong reduction of symptoms.

When initiating or increasing SSRIs or SNRIs, there are common nontoxic AEs that are not consistent with ST, including anxiety, restlessness, and irritability that may last for 2 weeks. The difference in toxic vs nontoxic reactions are the timing and rapid progression of symptoms. The toxic symptoms will start within hours of ingesting the offending agents(s) and progress rapidly to severe symptoms within 24 hours. Therefore, it is imperative to review AEs with the patient and or caregiver, so they may act as their own advocate and seek immediate assistance.

Differentials

There are symptoms specific to ST that can be used to differentiate it from other conditions. These include hyperthermia, bilateral symmetric clonus (inducible, spontaneous, ocular), and hyperreflexia.These criteria form the basis for Hunter criteria.

Differential diagnoses to consider include neuroleptic malignant syndrome; antidepressant initiation AEs; antidepressant discontinuation syndrome; malignant hyperthermia; anticholinergic toxicity; meningitis/encephalitis; sepsis; drug overdose; alcohol/benzodiazepine withdrawal; and preeclampsia. Neuroleptic malignant syndrome (NMS) is the disorder most often misdiagnosed as ST.Key elements that distinguish ST from NMS include the timing of the clinical course (NMS develops over days to weeks); the medications ingested (NMS from dopaminergic drugs); and the symptoms of NMS (bradyreflexia, bradykinesia, bradyphrenia, and no clonus).According to Gillman, serotonin toxicity is a manifestation of toxicity that is predictable and common with specific drug combinations, while NMS is a “rare idiosyncratic reaction to essentially normal doses and very rarely occurs after overdoses.”³⁵ Preeclampsia is a pregnancy complication that can mimic ST with symptoms of hypertension, clonus, and hyperreflexia. It has been estimated to complicate 2% to 8% of pregnancies and remains a principle cause of maternal and fetal morbidity and mortality.^36,37

Treatment

Mild-to-moderate symptoms usually resolve on their own 1 to 3 days after decreasing or stopping the offending drug. The timing will depend on the half-life or active metabolites of the drug. Treatment is largely supportive and may require treatment for control of agitation with benzodiazepines and IV fluids for dehydration/hypotension.¹⁴ In cases not responding to supportive care, treatment with oral cyproheptadine is recommended.¹⁴

There are other medications that have been used in treatment such as olanzapine, chlorpromazine, propranolol, bromocriptine, dantrolene, droperidol, and haloperidol, but their efficacy is unproven and not recommended.¹⁰ Chlorpromazine can cause hypotension and increase hyperthermia. Propranolol has a long duration of action, may cause a prolonged hypotension, and can mask tachycardia that can be used to monitor the effectiveness of treatment.¹⁰ Bromocriptine is a serotonin agonist and may exacerbate symptoms. Dantrolene has no effect on survival in animal models.¹⁰ Droperidol and haloperidol can worsen hyperthermia by inhibiting sweating.³⁸

Mechanical ventilation should be considered especially if muscle rigidity progresses and depressed respiratory function occurs. If the temperature starts to rise, immediate sedation, paralysis, mechanical ventilation, and cyproheptadine are administered.The overall goal is prevention of hyperthermia, which leads to multiorgan failure. A core temperature of ≥ 104°F is associated with neurologic cell death, and recovery is minimal.³² Consultation with an experienced toxicologist is strongly recommended.Antipyretics should not be used, because elevated temperature is centrally mediated from muscle rigidity. If presentation occurs within 1 hour, activated charcoal can be used for detoxification of potentially lethal amounts.

Warning Label Controversies

In 2006, the US Food and Drug Administration (FDA) issued an advisory warning against concurrently using a tryptan antimigraine drug and serotonin-mediated medications.³⁹ In 2018, a research team conducted a 14-year retrospective analysis on 20,000 patients who were coprescribed a tryptan drug with SSRIs or SNRIs.⁴⁰ The study reported that the risk of ST was rare and suggested that the FDA reconsider their advisory. There are several other controversial medications with a ST FDA warning label due to their mechanisms of action and inaccurate case reports.⁴¹

Human Poisonings

Consistent with the 2017 American Association of Poison Control Centers Toxic Exposure report, antidepressants continue to be in the top 5 substance classes most frequently involved in human exposures.⁴² Most accidental ingestions of antidepressants occur in toddlers, whereas intentional ingestions are usually done by adolesents.⁴³ Over the past 10 years, antidepressants are the No. 1 fastest growing category of human exposures in all age groups.⁴²

ST in the Pediatric Population

ST in the pediatric population mirrors that in adults.Differences include the inability of the child to report symptoms, lack of clinician awareness, and reluctance of adolescents to disclose recreational drug use.Management is the same as for adults, including discontinuing the offending drug, supportive care, adequate sedation, oxygen, IV fluids, and continuous cardiac monitoring. Sedation is weight based for benzodiazepines. Mild-to-moderate reactions require admission for observation. Severe reactions require admission to the ICU.

There have been at least 4 published case reports of children aged < 6 years with moderate-to-severe ST secondary to acute vilazodone ingestion.⁴⁴ The dosages included 5.5 to 37 mg/kg. All 4 patients had altered mental status, seizures, hyperthermia, mild clonus, tachycardia, and hypertension. They all survived with intensive care treatment, including intubation, sedation, cyproheptadine in 2 cases, activated charcoal and IV lorazepam in the other cases.

Direk and colleagues reported a case of a 12-year-old girl who was brought to the emergency department by her stepmother for seizurelike activity and was diagnosed with epilepsy and status epilepticus.⁴⁵ In the pediatric ICU she developed tachycardia, fever, agitation, dilated pupils, tremors, increased deep tendon reflexes, spontaneous clonus, and horizontal ocular movements. A detailed clinical history was retaken and revealed that the child had been prescribed risperidone 1 week before by the psychiatric clinic due to behavioral problems, including stealing money, lying, and running away from home and school. On further investigation, the stepmother was taking clomipramine and discovered 9 missing pills.

Pregnancy and Lactation

The American College of Obstetricians and Gynecologists recommends that clinicians screen patients at least once during the perinatal period for depression and anxiety symptoms, using a standardized, validated tool and complete a full assessment of mood and emotional well-being during the postpartum, including screening for postpartum depression and anxiety with a validated instrument.⁴⁶ Treatment with antidepressants is controversial. “Current evidence is generally reassuring and indicates that the absolute risks of negative infant outcomes are small except for PNAS [poor neonatal adaptation syndrome], which largely appears to be self-limited.”⁴⁷ Antidepressants cross the human placenta and fetal blood-brain barrier.⁴⁸ Several cases of infant toxicity from SSRIs have been reported with citalopram and escitalopram.^49,50 Symptoms included severe muscle rigidity, lethargy, tachycardia, QTc prolongation, altered consciousness, hypertonia, and seizures at birth. These mothers had taken an SSRI during pregnancy.

Conclusions

This article highlights some of the latest information on ST. Increased awareness of all clinicians and their patients may help decrease unnecessary comorbidities and death. Early identification of ST symptoms will increase the chances for survival, because of the rapid progression of symptoms within 24 hours. Most fatal reactions occur when combining MAOIs with SSRIs, SNRIs, or another MAOI. Overdose with an SSRI does not progress to the severe symptoms unless combined with another serotonin-elevating medication.

Education of all patients who are prescribed antidepressants must include awareness of the potential for serotonergic drug interactions, particularly from OTC medications, herbal medications, and illicit drugs. The diagnosis of ST is based on clinical findings and there must be a history of ingesting serotonin-elevating drug(s). Hunter Serotonin Toxicity Criteria is the gold standard for diagnosing symptoms along with consulting a toxicologist. Prevention of ST includes informed clinicians, patient education, careful prescribing and monitoring, and avoidance of multidrug regimens.

Serotonin, or 5-hydroxytryptamine (5-HT), is a chemical neurotransmitter in the central and peripheral nervous systems that was discovered in 1940s. ¹ O ne of the most widely studied chemical messengers , serotonin influences many physiologic functions in humans, including regulation of mood, sleep-wake cycle, appetite suppression, memory, emesis, breathing, cognition, blood coagulation, libido, and many other functions. ² In 1992, Insel and colleagues first document ed the toxic symptoms produced from too much serotonin in the central and peripheral nervous systems , naming it serotonin syndrome. ^3,4

Serotonin Syndrome

Experts in the fields of psychiatry, pharmacy, and toxicology refer to these symptoms as serotonin toxicity, because the symptoms result from the toxic effects of too much serotonin.^5-9 The term toxicity instead of syndrome “clarifies that it is a form of poisoning, just as lithium toxicity is a form of poisoning.”⁶ Therefore, serotonin toxicity (ST) can develop with administration of any serotonin-enhancing medication, including therapeutic use, polypharmacy, or accidental/intentional drug overdose.

The incidence of ST has increased over the past decade.^5,6,10,11 Several reasons explain this increase: (1) ST mirrors the increase in depression in the US populations^10,12,13; (2) There has been an increase in off-label antidepressant prescribing by both primary care and mental health providers^14-16; (3) the increased use of illicit drugs¹³; (4) an increase in suicide attempts with antidepressants¹⁷; and (5) increased use of opioids for pain management, including both prescription and illicit use.^11,14 This paper reviews the potential lethal combinations of commonly prescribed medications used to treat both veteran and nonveteran patients and includes the latest information on offending medications; a presentation of symptoms from in utero to adult; diagnostic criteria; and recommended treatments.

The Veterans Health Administration (VHA) and non-VHA health care providers can play a key role in identifying and preventing serotonin syndrome/ST by keeping abreast of the latest updates of potentially lethal drug combinations. Commonly prescribed medications with the potential for a reaction include antidepressants, anxiolytics, pain medications, antinausea medications, herbal medications, and over-the-counter (OTC) medications, such as cough suppressants. Patients may be at increased risk for ST due to the growth of polypharmacy management of comorbidities.

Antidepressants

Over the past decade, antidepressant use has increased substantially in the US,United Kingdom, and Canada.¹⁴ Also the types of antidepressants prescribed has changed and been replaced with the newer agents. The selective serotonin reuptake inhibitors (SSRIs) and selective norepinephrine reuptake inhibitors (SNRIs) have replaced the older tricyclics (TCAs) and monoamine oxidase inhibitors (MAOIs) as first-line treatments for depression due to their improved comparative efficacy, reduced mortality following overdose, adverse effects (AEs) that are more tolerable for most patients, and the SSRIs have no anticholinergic properties (except paroxetine) (Table 1).¹⁸

In 2017 the National Institute of Mental Health reported that about 17 million adults and 3 million adolescents (aged 11-18 years) experienced at least 1 episode of major depression.¹⁹ About 40% of US veterans will experience depression, which is 3 times higher than the rate of the general US population.¹² A random sampling survey conducted of about 17,000 active-duty service members by the US Department of Defense (DoD) from November 2015 to April 2016 revealed 9.4% reported depression.²⁰ Antidepressant usage in the US and among veterans continues to increase.^12,16 In 2018, the list of top US prescribed drugs, included sertraline (14th), citalopram (21st), trazodone (24th), and escitalopram (26th).²¹ Antidepressant prescribing in the US increased 18% from 2012 to 2017.²² This trend also continues within the military with a 40% increase of antidepressant use in the past decade.¹⁶

One reason for the increase in antidepressant use is off-label prescribing.^14,23 A sampling of about 2 billion psychiatric outpatient visits in a western portion of the US found 12.9% of the prescriptions filled were off-label.¹⁵ In Minnesota, off-label prescribing of antidepressants was found to contribute to an increase in drug interactions in elderly nursing home residents.²⁴ An investigation by the Military Times of the military community revealed off-label prescribing occurs not only with antidepressant medications, but also with anticonvulsants, antipsychotics, anti-anxiety drugs, and antiepileptic medications.¹⁴

A case report that brought ST to the forefront occurred in the 1980s and involved a college student.²⁵ She was initially diagnosed with the flu. Her symptoms progressed over a 24-hour period despite treatment, leading to seizures, hyperthermia, generalized clonus, muscle rigidity, respiratory failure, and death because of unrecognized ST. Her combination of serotonin-elevating drugs included meperidine, phenelzine, chlorpheniramine, and haldol. On autopsy, there were traces of cocaine found in some of her tissue samples.

Pathophysiology

Tryptophan is a precursor of serotonin and must be ingested from foods, including meats, dairy, fruits, and seeds. About 90% of all serotonin is made in the gastrointestinal epithelium and is the major component of the brain-gut axis.²⁶ Serotonin cannot cross the blood-brain barrier; therefore, it is synthesized and stored in presynaptic terminals around the midline of the brainstem.^1,26 Transport of serotonin is provided by serotonin transporter (SERT).^1,26,27 Once released, serotonin can either stimulate postsynaptic neuron receptors or is taken up into the presynaptic terminals for reuse. SSRI antidepressants, such as citalopram and paroxetine inhibit the reuptake of serotonin by binding to 2 different sites on the SERT thus allowing more available serotonin to be accessible to other neurons.²⁷ There are 7 families of serotonin receptors, 5-HT1 to 5-HT7 and at least 15 mammalian subtypes.^28,29 The majority of these receptors have been implicated in depression or depressive-like behavior as evidenced by the efficacy of increasing extracellular serotonin for the treatment of depression with SSRIs, SNRIs, TCAs, and MAOIs.²⁹ Three of the most studied receptors include 5-HT_IA,5-HT_1B,and 5-HT_2A.

Etiology

Most serotonin-induced drug fatalities occur when combining serotonergic drugs that work through different pathways (Table 2).³⁰ The most toxic combination of serotonin-enhancing drugs includes MAOIs taken with SSRIs or SNRIs, or a combination of 2 MAOIs.^5-9

Other potentially lethal combinations may includepolypharmacy with antidepressants, pain medications, OTC medications, and illicit drugs. Linezolid, a new synthetic antimicrobial, is considered to be a weak MAOI. Therefore, prescribing it with other serotonin-elevating agents has been reported to precipitate ST.¹⁸

Most cases of ST do not require hospitalization and can be managed by stopping the medication or decreasing the dose. Therapeutic doses of a single drug are highly unlikely to cause toxicity, although there have been reported cases of patients who are sensitive or more susceptible and develop symptoms after administration of a single agent and/or a dosage increase.

Delayed ST reactions have occurred because of a prolonged half-life of a drug, iron deficiency anemia, and coingestion of shorter acting serotonin antagonists.³¹ Most antidepressants have a short half-life (< 24 hours)except for fluoxetine. A decrease in iron may contribute to ST because iron is needed to process serotonin from tryptophan. An example of 2 shorter-acting serotonin antagonists include cyproheptadine and olanzapine. Cyproheptadine is used in the treatment of ST, and olanzapine is an antipsychotic.

Symptoms

Symptoms of ST range from mild to severe and include a combination of neuromuscular, autonomic, and mental status changes (Table 3).^5,10 Mild symptoms of ST can start within 1 to 2 hours after ingesting a medication that increases serotonin to a toxic state unless the drug has a long half-life (eg, fluoxetine). Sometimes mild symptoms of ST can be difficult to distinguish from common drug AEs, flu symptoms, or viruses. Patients taking therapeutic doses of SSRIs can experience serotonin symptoms, such as lower limb hyperreflexia or a few beats of ankle clonus without being toxic. One thing to remember is that not all patients will start with mild symptoms and may present in moderate or severe distress.

Moderate-to-severe ST symptoms require hospitalization, usually in the intensive care unit (ICU). At this stage, clonus progresses from the lower extremities to the upper body and becomes more generalized. Ocular clonus can be continuous, intermittent, or have a ping pong effect (short cycle, periodic, alternating lateral gaze).

Severe ST is life threatening and leads to multiorgan failure within hours if not treated. The patient is intubated to assist with breathing and sedated because excess agitation and muscular tremors can increase temperature, which is already elevated by the time the symptoms reach the severe state. Of note, hyperthermia is due to a noninfectious elevation of body temperature from hypertonicity, agitation, and muscle rigidity.A true core temperature > 105.8°F causes irreversible cell damage, cerebral injury, and death.^32,33 The patient can develop seizures and a coma. Multiorgan failure occurs, including rhabdomyolysis, myoglobinuria, renal failure, metabolic acidosis, acute respiratory distress, and disseminated intravascular coagulation.

Diagnosis

The diagnosis of ST is clinical and based on a history of ingesting serotonin-elevating medications and physical findings as per Hunter Serotonin Toxicity Criteria³⁴ (Table 4). An in-depth history needs to include previous and current prescriptions, indications of the prescriptions (eg, therapeutic, increase in dosage, suicide intent), OTC medications, and illicit drug use. Early recognition of symptoms, identification of serotonergic medications, and appropriate resuscitative measures lead to more successful outcomes. A serotonin drug level is ineffective and does not correlate with the dosage since serotonin does not cross the blood-brain barrier.

The type of drug determines the length and response of the episode. The drug(s) elimination half-lives need to be calculated along with the pharmacokinetic or pharmacodynamics; agonist, antagonist, reuptake inhibitor, etc. Many drugs have half-lives of < 24 hours; therefore, reducing or eliminating the offending drug(s) will result in a steady reduction of symptoms.Exceptions include medications with a longer activity, such as the irreversible MAOIs (eg, phenelzine, isocarboxazid) and drugs with a longer half-life, such as fluoxetine. These types of medications may have been stopped weeks earlier and may prolong reduction of symptoms.

When initiating or increasing SSRIs or SNRIs, there are common nontoxic AEs that are not consistent with ST, including anxiety, restlessness, and irritability that may last for 2 weeks. The difference in toxic vs nontoxic reactions are the timing and rapid progression of symptoms. The toxic symptoms will start within hours of ingesting the offending agents(s) and progress rapidly to severe symptoms within 24 hours. Therefore, it is imperative to review AEs with the patient and or caregiver, so they may act as their own advocate and seek immediate assistance.

Differentials

There are symptoms specific to ST that can be used to differentiate it from other conditions. These include hyperthermia, bilateral symmetric clonus (inducible, spontaneous, ocular), and hyperreflexia.These criteria form the basis for Hunter criteria.

Differential diagnoses to consider include neuroleptic malignant syndrome; antidepressant initiation AEs; antidepressant discontinuation syndrome; malignant hyperthermia; anticholinergic toxicity; meningitis/encephalitis; sepsis; drug overdose; alcohol/benzodiazepine withdrawal; and preeclampsia. Neuroleptic malignant syndrome (NMS) is the disorder most often misdiagnosed as ST.Key elements that distinguish ST from NMS include the timing of the clinical course (NMS develops over days to weeks); the medications ingested (NMS from dopaminergic drugs); and the symptoms of NMS (bradyreflexia, bradykinesia, bradyphrenia, and no clonus).According to Gillman, serotonin toxicity is a manifestation of toxicity that is predictable and common with specific drug combinations, while NMS is a “rare idiosyncratic reaction to essentially normal doses and very rarely occurs after overdoses.”³⁵ Preeclampsia is a pregnancy complication that can mimic ST with symptoms of hypertension, clonus, and hyperreflexia. It has been estimated to complicate 2% to 8% of pregnancies and remains a principle cause of maternal and fetal morbidity and mortality.^36,37

Treatment

Mild-to-moderate symptoms usually resolve on their own 1 to 3 days after decreasing or stopping the offending drug. The timing will depend on the half-life or active metabolites of the drug. Treatment is largely supportive and may require treatment for control of agitation with benzodiazepines and IV fluids for dehydration/hypotension.¹⁴ In cases not responding to supportive care, treatment with oral cyproheptadine is recommended.¹⁴

There are other medications that have been used in treatment such as olanzapine, chlorpromazine, propranolol, bromocriptine, dantrolene, droperidol, and haloperidol, but their efficacy is unproven and not recommended.¹⁰ Chlorpromazine can cause hypotension and increase hyperthermia. Propranolol has a long duration of action, may cause a prolonged hypotension, and can mask tachycardia that can be used to monitor the effectiveness of treatment.¹⁰ Bromocriptine is a serotonin agonist and may exacerbate symptoms. Dantrolene has no effect on survival in animal models.¹⁰ Droperidol and haloperidol can worsen hyperthermia by inhibiting sweating.³⁸

Mechanical ventilation should be considered especially if muscle rigidity progresses and depressed respiratory function occurs. If the temperature starts to rise, immediate sedation, paralysis, mechanical ventilation, and cyproheptadine are administered.The overall goal is prevention of hyperthermia, which leads to multiorgan failure. A core temperature of ≥ 104°F is associated with neurologic cell death, and recovery is minimal.³² Consultation with an experienced toxicologist is strongly recommended.Antipyretics should not be used, because elevated temperature is centrally mediated from muscle rigidity. If presentation occurs within 1 hour, activated charcoal can be used for detoxification of potentially lethal amounts.

Warning Label Controversies

In 2006, the US Food and Drug Administration (FDA) issued an advisory warning against concurrently using a tryptan antimigraine drug and serotonin-mediated medications.³⁹ In 2018, a research team conducted a 14-year retrospective analysis on 20,000 patients who were coprescribed a tryptan drug with SSRIs or SNRIs.⁴⁰ The study reported that the risk of ST was rare and suggested that the FDA reconsider their advisory. There are several other controversial medications with a ST FDA warning label due to their mechanisms of action and inaccurate case reports.⁴¹

Human Poisonings

Consistent with the 2017 American Association of Poison Control Centers Toxic Exposure report, antidepressants continue to be in the top 5 substance classes most frequently involved in human exposures.⁴² Most accidental ingestions of antidepressants occur in toddlers, whereas intentional ingestions are usually done by adolesents.⁴³ Over the past 10 years, antidepressants are the No. 1 fastest growing category of human exposures in all age groups.⁴²

ST in the Pediatric Population

ST in the pediatric population mirrors that in adults.Differences include the inability of the child to report symptoms, lack of clinician awareness, and reluctance of adolescents to disclose recreational drug use.Management is the same as for adults, including discontinuing the offending drug, supportive care, adequate sedation, oxygen, IV fluids, and continuous cardiac monitoring. Sedation is weight based for benzodiazepines. Mild-to-moderate reactions require admission for observation. Severe reactions require admission to the ICU.

There have been at least 4 published case reports of children aged < 6 years with moderate-to-severe ST secondary to acute vilazodone ingestion.⁴⁴ The dosages included 5.5 to 37 mg/kg. All 4 patients had altered mental status, seizures, hyperthermia, mild clonus, tachycardia, and hypertension. They all survived with intensive care treatment, including intubation, sedation, cyproheptadine in 2 cases, activated charcoal and IV lorazepam in the other cases.

Direk and colleagues reported a case of a 12-year-old girl who was brought to the emergency department by her stepmother for seizurelike activity and was diagnosed with epilepsy and status epilepticus.⁴⁵ In the pediatric ICU she developed tachycardia, fever, agitation, dilated pupils, tremors, increased deep tendon reflexes, spontaneous clonus, and horizontal ocular movements. A detailed clinical history was retaken and revealed that the child had been prescribed risperidone 1 week before by the psychiatric clinic due to behavioral problems, including stealing money, lying, and running away from home and school. On further investigation, the stepmother was taking clomipramine and discovered 9 missing pills.

Pregnancy and Lactation

The American College of Obstetricians and Gynecologists recommends that clinicians screen patients at least once during the perinatal period for depression and anxiety symptoms, using a standardized, validated tool and complete a full assessment of mood and emotional well-being during the postpartum, including screening for postpartum depression and anxiety with a validated instrument.⁴⁶ Treatment with antidepressants is controversial. “Current evidence is generally reassuring and indicates that the absolute risks of negative infant outcomes are small except for PNAS [poor neonatal adaptation syndrome], which largely appears to be self-limited.”⁴⁷ Antidepressants cross the human placenta and fetal blood-brain barrier.⁴⁸ Several cases of infant toxicity from SSRIs have been reported with citalopram and escitalopram.^49,50 Symptoms included severe muscle rigidity, lethargy, tachycardia, QTc prolongation, altered consciousness, hypertonia, and seizures at birth. These mothers had taken an SSRI during pregnancy.

Conclusions

This article highlights some of the latest information on ST. Increased awareness of all clinicians and their patients may help decrease unnecessary comorbidities and death. Early identification of ST symptoms will increase the chances for survival, because of the rapid progression of symptoms within 24 hours. Most fatal reactions occur when combining MAOIs with SSRIs, SNRIs, or another MAOI. Overdose with an SSRI does not progress to the severe symptoms unless combined with another serotonin-elevating medication.

Education of all patients who are prescribed antidepressants must include awareness of the potential for serotonergic drug interactions, particularly from OTC medications, herbal medications, and illicit drugs. The diagnosis of ST is based on clinical findings and there must be a history of ingesting serotonin-elevating drug(s). Hunter Serotonin Toxicity Criteria is the gold standard for diagnosing symptoms along with consulting a toxicologist. Prevention of ST includes informed clinicians, patient education, careful prescribing and monitoring, and avoidance of multidrug regimens.

Serotonin, or 5-hydroxytryptamine (5-HT), is a chemical neurotransmitter in the central and peripheral nervous systems that was discovered in 1940s. ¹ O ne of the most widely studied chemical messengers , serotonin influences many physiologic functions in humans, including regulation of mood, sleep-wake cycle, appetite suppression, memory, emesis, breathing, cognition, blood coagulation, libido, and many other functions. ² In 1992, Insel and colleagues first document ed the toxic symptoms produced from too much serotonin in the central and peripheral nervous systems , naming it serotonin syndrome. ^3,4

Serotonin Syndrome

Experts in the fields of psychiatry, pharmacy, and toxicology refer to these symptoms as serotonin toxicity, because the symptoms result from the toxic effects of too much serotonin.^5-9 The term toxicity instead of syndrome “clarifies that it is a form of poisoning, just as lithium toxicity is a form of poisoning.”⁶ Therefore, serotonin toxicity (ST) can develop with administration of any serotonin-enhancing medication, including therapeutic use, polypharmacy, or accidental/intentional drug overdose.

The incidence of ST has increased over the past decade.^5,6,10,11 Several reasons explain this increase: (1) ST mirrors the increase in depression in the US populations^10,12,13; (2) There has been an increase in off-label antidepressant prescribing by both primary care and mental health providers^14-16; (3) the increased use of illicit drugs¹³; (4) an increase in suicide attempts with antidepressants¹⁷; and (5) increased use of opioids for pain management, including both prescription and illicit use.^11,14 This paper reviews the potential lethal combinations of commonly prescribed medications used to treat both veteran and nonveteran patients and includes the latest information on offending medications; a presentation of symptoms from in utero to adult; diagnostic criteria; and recommended treatments.

The Veterans Health Administration (VHA) and non-VHA health care providers can play a key role in identifying and preventing serotonin syndrome/ST by keeping abreast of the latest updates of potentially lethal drug combinations. Commonly prescribed medications with the potential for a reaction include antidepressants, anxiolytics, pain medications, antinausea medications, herbal medications, and over-the-counter (OTC) medications, such as cough suppressants. Patients may be at increased risk for ST due to the growth of polypharmacy management of comorbidities.

Antidepressants

Over the past decade, antidepressant use has increased substantially in the US,United Kingdom, and Canada.¹⁴ Also the types of antidepressants prescribed has changed and been replaced with the newer agents. The selective serotonin reuptake inhibitors (SSRIs) and selective norepinephrine reuptake inhibitors (SNRIs) have replaced the older tricyclics (TCAs) and monoamine oxidase inhibitors (MAOIs) as first-line treatments for depression due to their improved comparative efficacy, reduced mortality following overdose, adverse effects (AEs) that are more tolerable for most patients, and the SSRIs have no anticholinergic properties (except paroxetine) (Table 1).¹⁸

In 2017 the National Institute of Mental Health reported that about 17 million adults and 3 million adolescents (aged 11-18 years) experienced at least 1 episode of major depression.¹⁹ About 40% of US veterans will experience depression, which is 3 times higher than the rate of the general US population.¹² A random sampling survey conducted of about 17,000 active-duty service members by the US Department of Defense (DoD) from November 2015 to April 2016 revealed 9.4% reported depression.²⁰ Antidepressant usage in the US and among veterans continues to increase.^12,16 In 2018, the list of top US prescribed drugs, included sertraline (14th), citalopram (21st), trazodone (24th), and escitalopram (26th).²¹ Antidepressant prescribing in the US increased 18% from 2012 to 2017.²² This trend also continues within the military with a 40% increase of antidepressant use in the past decade.¹⁶

One reason for the increase in antidepressant use is off-label prescribing.^14,23 A sampling of about 2 billion psychiatric outpatient visits in a western portion of the US found 12.9% of the prescriptions filled were off-label.¹⁵ In Minnesota, off-label prescribing of antidepressants was found to contribute to an increase in drug interactions in elderly nursing home residents.²⁴ An investigation by the Military Times of the military community revealed off-label prescribing occurs not only with antidepressant medications, but also with anticonvulsants, antipsychotics, anti-anxiety drugs, and antiepileptic medications.¹⁴

A case report that brought ST to the forefront occurred in the 1980s and involved a college student.²⁵ She was initially diagnosed with the flu. Her symptoms progressed over a 24-hour period despite treatment, leading to seizures, hyperthermia, generalized clonus, muscle rigidity, respiratory failure, and death because of unrecognized ST. Her combination of serotonin-elevating drugs included meperidine, phenelzine, chlorpheniramine, and haldol. On autopsy, there were traces of cocaine found in some of her tissue samples.

Pathophysiology

Tryptophan is a precursor of serotonin and must be ingested from foods, including meats, dairy, fruits, and seeds. About 90% of all serotonin is made in the gastrointestinal epithelium and is the major component of the brain-gut axis.²⁶ Serotonin cannot cross the blood-brain barrier; therefore, it is synthesized and stored in presynaptic terminals around the midline of the brainstem.^1,26 Transport of serotonin is provided by serotonin transporter (SERT).^1,26,27 Once released, serotonin can either stimulate postsynaptic neuron receptors or is taken up into the presynaptic terminals for reuse. SSRI antidepressants, such as citalopram and paroxetine inhibit the reuptake of serotonin by binding to 2 different sites on the SERT thus allowing more available serotonin to be accessible to other neurons.²⁷ There are 7 families of serotonin receptors, 5-HT1 to 5-HT7 and at least 15 mammalian subtypes.^28,29 The majority of these receptors have been implicated in depression or depressive-like behavior as evidenced by the efficacy of increasing extracellular serotonin for the treatment of depression with SSRIs, SNRIs, TCAs, and MAOIs.²⁹ Three of the most studied receptors include 5-HT_IA,5-HT_1B,and 5-HT_2A.

Etiology

Most serotonin-induced drug fatalities occur when combining serotonergic drugs that work through different pathways (Table 2).³⁰ The most toxic combination of serotonin-enhancing drugs includes MAOIs taken with SSRIs or SNRIs, or a combination of 2 MAOIs.^5-9

Other potentially lethal combinations may includepolypharmacy with antidepressants, pain medications, OTC medications, and illicit drugs. Linezolid, a new synthetic antimicrobial, is considered to be a weak MAOI. Therefore, prescribing it with other serotonin-elevating agents has been reported to precipitate ST.¹⁸

Most cases of ST do not require hospitalization and can be managed by stopping the medication or decreasing the dose. Therapeutic doses of a single drug are highly unlikely to cause toxicity, although there have been reported cases of patients who are sensitive or more susceptible and develop symptoms after administration of a single agent and/or a dosage increase.

Delayed ST reactions have occurred because of a prolonged half-life of a drug, iron deficiency anemia, and coingestion of shorter acting serotonin antagonists.³¹ Most antidepressants have a short half-life (< 24 hours)except for fluoxetine. A decrease in iron may contribute to ST because iron is needed to process serotonin from tryptophan. An example of 2 shorter-acting serotonin antagonists include cyproheptadine and olanzapine. Cyproheptadine is used in the treatment of ST, and olanzapine is an antipsychotic.

Symptoms

Symptoms of ST range from mild to severe and include a combination of neuromuscular, autonomic, and mental status changes (Table 3).^5,10 Mild symptoms of ST can start within 1 to 2 hours after ingesting a medication that increases serotonin to a toxic state unless the drug has a long half-life (eg, fluoxetine). Sometimes mild symptoms of ST can be difficult to distinguish from common drug AEs, flu symptoms, or viruses. Patients taking therapeutic doses of SSRIs can experience serotonin symptoms, such as lower limb hyperreflexia or a few beats of ankle clonus without being toxic. One thing to remember is that not all patients will start with mild symptoms and may present in moderate or severe distress.

Moderate-to-severe ST symptoms require hospitalization, usually in the intensive care unit (ICU). At this stage, clonus progresses from the lower extremities to the upper body and becomes more generalized. Ocular clonus can be continuous, intermittent, or have a ping pong effect (short cycle, periodic, alternating lateral gaze).

Severe ST is life threatening and leads to multiorgan failure within hours if not treated. The patient is intubated to assist with breathing and sedated because excess agitation and muscular tremors can increase temperature, which is already elevated by the time the symptoms reach the severe state. Of note, hyperthermia is due to a noninfectious elevation of body temperature from hypertonicity, agitation, and muscle rigidity.A true core temperature > 105.8°F causes irreversible cell damage, cerebral injury, and death.^32,33 The patient can develop seizures and a coma. Multiorgan failure occurs, including rhabdomyolysis, myoglobinuria, renal failure, metabolic acidosis, acute respiratory distress, and disseminated intravascular coagulation.

Diagnosis

The diagnosis of ST is clinical and based on a history of ingesting serotonin-elevating medications and physical findings as per Hunter Serotonin Toxicity Criteria³⁴ (Table 4). An in-depth history needs to include previous and current prescriptions, indications of the prescriptions (eg, therapeutic, increase in dosage, suicide intent), OTC medications, and illicit drug use. Early recognition of symptoms, identification of serotonergic medications, and appropriate resuscitative measures lead to more successful outcomes. A serotonin drug level is ineffective and does not correlate with the dosage since serotonin does not cross the blood-brain barrier.

The type of drug determines the length and response of the episode. The drug(s) elimination half-lives need to be calculated along with the pharmacokinetic or pharmacodynamics; agonist, antagonist, reuptake inhibitor, etc. Many drugs have half-lives of < 24 hours; therefore, reducing or eliminating the offending drug(s) will result in a steady reduction of symptoms.Exceptions include medications with a longer activity, such as the irreversible MAOIs (eg, phenelzine, isocarboxazid) and drugs with a longer half-life, such as fluoxetine. These types of medications may have been stopped weeks earlier and may prolong reduction of symptoms.

When initiating or increasing SSRIs or SNRIs, there are common nontoxic AEs that are not consistent with ST, including anxiety, restlessness, and irritability that may last for 2 weeks. The difference in toxic vs nontoxic reactions are the timing and rapid progression of symptoms. The toxic symptoms will start within hours of ingesting the offending agents(s) and progress rapidly to severe symptoms within 24 hours. Therefore, it is imperative to review AEs with the patient and or caregiver, so they may act as their own advocate and seek immediate assistance.

Differentials

There are symptoms specific to ST that can be used to differentiate it from other conditions. These include hyperthermia, bilateral symmetric clonus (inducible, spontaneous, ocular), and hyperreflexia.These criteria form the basis for Hunter criteria.

Differential diagnoses to consider include neuroleptic malignant syndrome; antidepressant initiation AEs; antidepressant discontinuation syndrome; malignant hyperthermia; anticholinergic toxicity; meningitis/encephalitis; sepsis; drug overdose; alcohol/benzodiazepine withdrawal; and preeclampsia. Neuroleptic malignant syndrome (NMS) is the disorder most often misdiagnosed as ST.Key elements that distinguish ST from NMS include the timing of the clinical course (NMS develops over days to weeks); the medications ingested (NMS from dopaminergic drugs); and the symptoms of NMS (bradyreflexia, bradykinesia, bradyphrenia, and no clonus).According to Gillman, serotonin toxicity is a manifestation of toxicity that is predictable and common with specific drug combinations, while NMS is a “rare idiosyncratic reaction to essentially normal doses and very rarely occurs after overdoses.”³⁵ Preeclampsia is a pregnancy complication that can mimic ST with symptoms of hypertension, clonus, and hyperreflexia. It has been estimated to complicate 2% to 8% of pregnancies and remains a principle cause of maternal and fetal morbidity and mortality.^36,37

Treatment

Mild-to-moderate symptoms usually resolve on their own 1 to 3 days after decreasing or stopping the offending drug. The timing will depend on the half-life or active metabolites of the drug. Treatment is largely supportive and may require treatment for control of agitation with benzodiazepines and IV fluids for dehydration/hypotension.¹⁴ In cases not responding to supportive care, treatment with oral cyproheptadine is recommended.¹⁴

There are other medications that have been used in treatment such as olanzapine, chlorpromazine, propranolol, bromocriptine, dantrolene, droperidol, and haloperidol, but their efficacy is unproven and not recommended.¹⁰ Chlorpromazine can cause hypotension and increase hyperthermia. Propranolol has a long duration of action, may cause a prolonged hypotension, and can mask tachycardia that can be used to monitor the effectiveness of treatment.¹⁰ Bromocriptine is a serotonin agonist and may exacerbate symptoms. Dantrolene has no effect on survival in animal models.¹⁰ Droperidol and haloperidol can worsen hyperthermia by inhibiting sweating.³⁸

Mechanical ventilation should be considered especially if muscle rigidity progresses and depressed respiratory function occurs. If the temperature starts to rise, immediate sedation, paralysis, mechanical ventilation, and cyproheptadine are administered.The overall goal is prevention of hyperthermia, which leads to multiorgan failure. A core temperature of ≥ 104°F is associated with neurologic cell death, and recovery is minimal.³² Consultation with an experienced toxicologist is strongly recommended.Antipyretics should not be used, because elevated temperature is centrally mediated from muscle rigidity. If presentation occurs within 1 hour, activated charcoal can be used for detoxification of potentially lethal amounts.

Warning Label Controversies

In 2006, the US Food and Drug Administration (FDA) issued an advisory warning against concurrently using a tryptan antimigraine drug and serotonin-mediated medications.³⁹ In 2018, a research team conducted a 14-year retrospective analysis on 20,000 patients who were coprescribed a tryptan drug with SSRIs or SNRIs.⁴⁰ The study reported that the risk of ST was rare and suggested that the FDA reconsider their advisory. There are several other controversial medications with a ST FDA warning label due to their mechanisms of action and inaccurate case reports.⁴¹

Human Poisonings

Consistent with the 2017 American Association of Poison Control Centers Toxic Exposure report, antidepressants continue to be in the top 5 substance classes most frequently involved in human exposures.⁴² Most accidental ingestions of antidepressants occur in toddlers, whereas intentional ingestions are usually done by adolesents.⁴³ Over the past 10 years, antidepressants are the No. 1 fastest growing category of human exposures in all age groups.⁴²

ST in the Pediatric Population

ST in the pediatric population mirrors that in adults.Differences include the inability of the child to report symptoms, lack of clinician awareness, and reluctance of adolescents to disclose recreational drug use.Management is the same as for adults, including discontinuing the offending drug, supportive care, adequate sedation, oxygen, IV fluids, and continuous cardiac monitoring. Sedation is weight based for benzodiazepines. Mild-to-moderate reactions require admission for observation. Severe reactions require admission to the ICU.

There have been at least 4 published case reports of children aged < 6 years with moderate-to-severe ST secondary to acute vilazodone ingestion.⁴⁴ The dosages included 5.5 to 37 mg/kg. All 4 patients had altered mental status, seizures, hyperthermia, mild clonus, tachycardia, and hypertension. They all survived with intensive care treatment, including intubation, sedation, cyproheptadine in 2 cases, activated charcoal and IV lorazepam in the other cases.

Direk and colleagues reported a case of a 12-year-old girl who was brought to the emergency department by her stepmother for seizurelike activity and was diagnosed with epilepsy and status epilepticus.⁴⁵ In the pediatric ICU she developed tachycardia, fever, agitation, dilated pupils, tremors, increased deep tendon reflexes, spontaneous clonus, and horizontal ocular movements. A detailed clinical history was retaken and revealed that the child had been prescribed risperidone 1 week before by the psychiatric clinic due to behavioral problems, including stealing money, lying, and running away from home and school. On further investigation, the stepmother was taking clomipramine and discovered 9 missing pills.

Pregnancy and Lactation

The American College of Obstetricians and Gynecologists recommends that clinicians screen patients at least once during the perinatal period for depression and anxiety symptoms, using a standardized, validated tool and complete a full assessment of mood and emotional well-being during the postpartum, including screening for postpartum depression and anxiety with a validated instrument.⁴⁶ Treatment with antidepressants is controversial. “Current evidence is generally reassuring and indicates that the absolute risks of negative infant outcomes are small except for PNAS [poor neonatal adaptation syndrome], which largely appears to be self-limited.”⁴⁷ Antidepressants cross the human placenta and fetal blood-brain barrier.⁴⁸ Several cases of infant toxicity from SSRIs have been reported with citalopram and escitalopram.^49,50 Symptoms included severe muscle rigidity, lethargy, tachycardia, QTc prolongation, altered consciousness, hypertonia, and seizures at birth. These mothers had taken an SSRI during pregnancy.

Conclusions

This article highlights some of the latest information on ST. Increased awareness of all clinicians and their patients may help decrease unnecessary comorbidities and death. Early identification of ST symptoms will increase the chances for survival, because of the rapid progression of symptoms within 24 hours. Most fatal reactions occur when combining MAOIs with SSRIs, SNRIs, or another MAOI. Overdose with an SSRI does not progress to the severe symptoms unless combined with another serotonin-elevating medication.

Education of all patients who are prescribed antidepressants must include awareness of the potential for serotonergic drug interactions, particularly from OTC medications, herbal medications, and illicit drugs. The diagnosis of ST is based on clinical findings and there must be a history of ingesting serotonin-elevating drug(s). Hunter Serotonin Toxicity Criteria is the gold standard for diagnosing symptoms along with consulting a toxicologist. Prevention of ST includes informed clinicians, patient education, careful prescribing and monitoring, and avoidance of multidrug regimens.